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The contribution of the meningeal immune interface to neuroinflammation in traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a major cause of disability and mortality worldwide, particularly among the elderly, yet our mechanistic understanding of what renders the post-traumatic brain vulnerable to poor outcomes, and susceptible to neurological disease, is incomplete. It is well established that dysregulated and sustained immune responses elicit negative consequences after TBI; however, our understanding of the neuroimmune interface that facilitates crosstalk between central and peripheral immune reservoirs is in its infancy. The meninges serve as the interface between the brain and the immune system, facilitating important bi-directional roles in both healthy and disease settings. It has been previously shown that disruption of this system exacerbates neuroinflammation in age-related neurodegenerative disorders such as Alzheimer’s disease; however, we have an incomplete understanding of how the meningeal compartment influences immune responses after TBI. In this manuscript, we will offer a detailed overview of the holistic nature of neuroinflammatory responses in TBI, including hallmark features observed across clinical and animal models. We will highlight the structure and function of the meningeal lymphatic system, including its role in immuno-surveillance and immune responses within the meninges and the brain. We will provide a comprehensive update on our current knowledge of meningeal-derived responses across the spectrum of TBI, and identify new avenues for neuroimmune modulation within the neurotrauma field.

Background

Traumatic brain injury (TBI) is a leading cause of death and disability, posing a significant socioeconomic and public health burden, with an estimated 64–74 million people sustaining a TBI each year [1, 2]. While the prevalence of TBI is centered around young adults and the elderly [3, 4], the consequences of TBI are more severe in aged populations. Slower recovery, worse functional, cognitive, and psychosocial outcomes, all highlight the influence of age on overall TBI pathogenesis [5,6,7,8,9,10,11]. Strikingly, there were 69,473 TBI-related deaths in the United States alone in 2021 [12], emphasizing the need for disease modifying interventions. There are no comprehensive pharmacological treatments for TBI, with the diversity of injury still considered a significant barrier toward the translation of effective therapeutics [13]. Although TBI can be influenced by many variables, it is accepted that neuroinflammation contributes to negative outcomes after TBI. Evidence suggests that the synergistic functioning of innate and adaptive immune cells, crucial for orchestrating and sustaining a healthy brain microenvironment, becomes dysfunctional after TBI. This dysfunction results in sustained, uncontrolled neuroinflammatory responses which detrimentally affect outcomes and recovery timeframes. Indeed, therapies targeting inflammatory responses display efficacy in preclinical and single-center trials; however, they fail to show improvement in larger multicenter clinical trials [14, 15]. This may be due to the fact that the majority of preclinical TBI studies tend to analyze these cellular responses individually, with interventions focused on targeting a singular cell modality. It is now evident that neuroinflammatory responses in TBI are not confined to a single cell type, and it is more likely that a combination of complex cellular interactions determines the nature of inflammatory cascades. Therefore, in order to develop more effective therapeutics, we require a greater understanding of the bi-directional crosstalk between the innate and adaptive immune response and how they contribute holistically to TBI-induced neuroinflammation.

Neuroinflammation in TBI

The complexity and challenges in understanding cellular interactions and signaling cascades in TBI is largely due to the heterogenous nature of injury. Primary injury causes brain lesions from fractures, intracranial hemorrhage, epidural and subdural hematoma, brain contusion and direct mechanical damage to neural tissue. Secondary injury occurs immediately following head impact, initiating cascades including neuroinflammation that can persist for weeks and even years, contributing to neurological impairment. Temporally, primary injury results in blood–brain barrier (BBB) dysfunction, neural damage, and release of endogenous damage-associated molecular patterns (DAMPs). These DAMPs subsequently engage pattern recognition receptors (PRR), such as the toll like receptors (TLRs) on innate (microglia/astrocytes) or adaptive (myeloid/lymphoid) cells, leading to their immune activation. The molecular diversity of DAMPs binding PRRs is vast (reviewed in [16]), and their significance after trauma is critical, with DAMP level correlating with injury severity and inversely related to clinical outcomes [17]. Indeed, clinical insights offer invaluable translational knowledge to identify secondary injury triggers and processes, information that may identify avenues for therapeutic intervention.

Clinical hallmarks of neuroinflammation in TBI

Physical trauma to the brain causes BBB disruption, with increased fibrinogen, immunoglobulin and heightened cerebrospinal fluid (CSF) to serum albumin quotients detectable within hours of clinical evaluation, persisting for weeks or even years [18,19,20,21,22,23,24,25,26]. Increases in serum and CSF levels of brain specific glial fibrillary acid protein (GFAP), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCH-L1) and S100 calcium-binding protein B (S100B) are correlated with early barrier permeability [20, 27]. Similarly, increased CSF levels of matrix metalloproteinases (MMPs) [28] and the complement mediators C3, factor B and sC5b-9 are also associated with BBB dysfunction [23, 29]. The CSF of severe TBI patients also contains DAMPs, PRRs and mediators downstream from PRR activation, with elevated levels of high mobility group protein B1 (HMGB1) [30,31,32], double stranded DNA (dsDNA), absent in melanoma 2 (AIM2), apoptosis-associated speck-like protein (ASC), NLR Family Pyrin Domain Containing 1 (NLRP1), and caspase-1 [33, 34]. Fluid biomarkers (CSF/serum/blood) show temporal increases in cytokines and chemokines, including members of respective interferon, interleukin, tumor necrosis factor, transforming growth factor and C-C motif ligand families (Table 1).

Table 1 Cytokines and chemokines modulating neuroinflammation in clinical TBI

Indeed, tissue samples from patients with TBI indicate that this inflammatory response is composed of both innate and adaptive cellular elements, including monocytes/macrophages, reactive microglia, polymorphonuclear cells, and CD4+, CD8+ T cells [83,84,85,86,87,88]. Using positron emission tomography (PET) scans, TBI patients show elevated translocator protein (TSPO) expression in microglia, demonstrating microglial activation which could be seen up to 17 years after injury [89, 90]. Indeed, in brain tissue, activated microglia (CD68+, CD11b+, TMEM119+) are highly expressed after injury across acute and chronic timepoints [83, 85, 91,92,93,94], alongside markers for toll like receptor (TLR) signaling including TLR4 and myeloid differentiation primary response 88 (Myd88) [95, 96]. Peripheral cell contributions are observed in blood samples after TBI, with acute decreases of the number CD4+ and CD8+ and natural killer (NK) cells, followed by transient increases in T regulatory (Treg) cells after injury [35, 97,98,99,100]. The temporal series of these responses may be influenced by injury severity, with expansion of Th17-type CD4 T cells alongside IL-17 and IL-22, seen at 5 days post injury [35]. Concurrently NK cells have reduced T-bet expression and lower IFNγ and TNFα, all indicating cell specific responses after TBI [35].

Hallmarks of neuroinflammation in animal models of TBI

Animal models have proven invaluable for studying TBI and unraveling the complicated mechanisms underlying both primary and secondary injuries. Similar to clinical studies, pre-clinical models show BBB permeability within hours, with spontaneous closure at approximately 7–10 days post-injury [101,102,103,104,105]. Mechanistically, TBI has been shown to affect processes at the neurovascular unit, with reductions in tight junction proteins (claudins, occludins) and pericyte loss [104, 106,107,108]. Across the spectrum of TBI models, various signals and triggers are elevated following injury, including DAMPS, cytokines, chemokines and soluble factors similar to those previously identified in clinical studies. Critically, their time and cell dependent function can be influenced by a myriad of context dependent factors (Fig. 1). Broadly, experimental TBI increases levels of DAMPs including HMGB1, ATP, heat-shock, GM-CSF, mtDNA and S100 proteins and their receptors such as TLRs and receptors of advanced glycosylation end-products (RAGE) and purinergic receptors. In addition, alterations in levels of proinflammatory cytokines TNF-α, IL-1β, IL-6, IL-18, IFNγ, Type-I interferons (IFNs), anti-inflammatory cytokines Arg-1, IL-4, IL-10, TGF-β and chemokines IL-8, MCP1, CCL2, CCL5, CXCL2 are all involved within the holistic nature of inflammation in TBI models (detailed review in [14, 109, 110]).

Fig. 1
figure 1

Hallmarks of neuroinflammation in Traumatic Brain Injury. Summary of hallmark characteristics that encompass the holistic nature of TBI-induced neuroinflammation. Based on decades of clinical research and mechanistic knowledge gained from the diverse range of injury models, key neuroinflammatory events include: barrier dysfunction, immune triggers and signaling, neural damage or release of soluble factors, neutrophil infiltration, monocyte recruitment, resident CNS microglial and astrocyte responses and activation of T and B cell responses. Importantly, all areas of this neuroinflammatory wheel can be influenced by context dependent factors, and should be considered across the spectrum of the neurotrauma field

Innate CNS responses

Microglia are resident central nervous system (CNS) immune cells, making about 10–13% of the cell population in the mouse and human brain [111, 112]. Their primary functions can be grouped to include surveillance, phagocytosis, and the secretion of soluble factors [113]. To determine functionality, microglia react to changes and context specific stimuli within CNS, eliciting a diverse array of tailored responses. Indeed, advancements in technologies (transcriptomics, proteomics and metabolomics) have highlighted that categorizing microglia into simplistic dichotomies like "good or bad" or "M1 or M2" does not adequately capture the full spectrum of microglial states across disease settings, and that updated nomenclatures and terminologies are warranted [113]. We agree with this principle, and to that extent, in assessing the role of microglia in pre-clinical TBI, we use the term Trauma Associated Microglia (TAM) to characterize the unique functionality of microglia in TBI versus other disease contexts (Fig. 1).

In healthy environments, microglia surveil their environment and can aid in synaptic remodeling, cell survival, and controlled phagocytosis removing CNS debris and waste products [114,115,116]. Morphologically, microglia are described as ‘ramified’ in their normal homeostatic state, and transform to a spectrum of morphologies during disease. In models of TBI, a dynamic range of TAMs are observed at both acute and chronic timepoints, initially clearing necrotic debris by adopting phagocytic states in response to ATP mediated purinergic signaling [117,118,119]. In the days and weeks following TBI, microglial cells undertake various functions, including, but not limited to, initiating immune responses, synaptic engulfment and clearance phagocytosis, influencing neuronal activity through bidirectional synaptic contact with neurons, and the potential to promote neurogenesis [120,121,122,123]. This dynamic functionality is generally delineated by the expression of Cd11b, CD68, CD86 and MHCII markers and accompanied by the release of proinflammatory mediators like TNF-α, IL-1β, NOX, IFNs or alternatively the expression of CD206 and Arg-1 markers and the release of anti-inflammatory factors including IL-10 and TGFβ [117, 121, 124,125,126,127,128,129]. Mechanistically, this functionality is determined by immune triggers that signal microglia to undergo morphological alterations resulting in highly activated states where they release soluble factors [118, 130]. Specifically, microglia are shown to respond to DAMPs activating PRRs, with TBI upregulating HMGB1, TLR2, TLR4 and NF-κB [31, 131,132,133]. Moreover, TLR2- and TLR4-deficient mice display decreased levels of TNF-α, IL-1, IL-6 and NF-κB signaling, evidencing their role in the TBI-induced pro-inflammatory response [134, 135]. In addition to TLRs, purinergic receptors P2Y6, P2Y12, and P2X4, detect ATP released from damaged cells and influence microglial responses after TBI [118, 119, 136]. Alongside the production of cytokines and chemokines, TAM also adopt functional states that promote oxidative stress through chronic NOX2 activation [137, 138]. In recent times, pharmacological depletion of microglia in the subacute and chronic timepoints after TBI is shown to be neuroprotective and improves outcomes [127, 139], underscoring the key role they play in deleterious TBI-induced neuroinflammatory responses.

Similar to microglia, astrocytes undergo morphological, molecular, and functional remodeling, with their classification now determined by the sum of their multi-factorial impact in context specific pathological settings [140]. In healthy contexts, astrocytes contribute to immune signaling, synaptogenesis regulation, BBB formation and maintenance, neurotransmitter recycling, ion and water homeostasis, and blood flow control [141,142,143,144,145]. In TBI, astrocytes are best known for the formation of the glial scar as a protective mechanism to limit secondary injury and promote regeneration [104, 146,147,148,149]. Astrogliosis is categorized by increased GFAP+ and vimentin across TBI models, yet away from the glial scar, the morphological significance of this gliosis is temporally and spatially dynamic [14]. They contribute to brain edema after injury [150,151,152], and contain decreased expression of GLT-1, GLAST and EAAT1/2, evidencing their role in TBI-induced glutamate dysregulation [153,154,155,156]. They also contribute directly to immune responses through DAMP/TLRs signaling as well as proinflammatory cytokine and chronic complement production after TBI [157,158,159,160]. Recent advances in high throughput sequencing and ‘omic analysis has generated datasets to begin to unravel the context specific nature of astrocytes in TBI [127, 161,162,163,164], yet these studies are still in early stages, especially when considering the range of heterogeneous immune responses that underpin the hallmark characteristics of TBI (Fig. 1). Furthermore, these responses often involve more than just a single cell type, exhibiting bidirectional communication, as evidenced by HMGB1 release from necrotic neurons, activating microglial TLR4, and subsequently increasing levels of astrocytic aquaporin-4 (AQP4), influencing BBB dynamics after TBI [31]. Indeed, this communication is now being explored in disease settings, with microglial release of C1q, IL1β and TNFα shown to transform astrocytes into neurotoxic states via their secretion of lipids contained in APOE and APOJ [165,166,167]. Blockade of this interaction is beneficial after stroke [168], suggesting studies of this pathway in TBI may yield promising targets to reduce inflammation mediated cell death pathways.

Adaptive immune responses

Peripheral interactions and cell specific processes play important roles in the overall neuroinflammatory response in TBI. Temporally, within minutes an initial wave of neutrophils crosses the BBB to phagocytose injured tissue, followed by potent chemoattractant signals that encourage the migration and infiltration of peripheral macrophages and lymphocytes (Fig. 1). The temporal series of these cellular events within the brain parenchyma has been extensively reviewed elsewhere [169, 170]. Within the scope of this review, we would like to discuss the contribution of the adaptive immune response in relation to its interaction at meningeal barriers, including the recently discovered immune rich lymphatic vessel interface.

Meningeal structures and barriers

The meninges, essential components of the CNS's protective and functional architecture, are composed of three distinct layers: the innermost pia mater, the intermediate arachnoid, and the outer dura mater. Structurally, the dura predominantly comprises collagen fibers that anchor it to the skull, as well as thin layer of fibroblasts demarcating the dura from the arachnoid [171]. In addition, the dura contains fenestrated blood vessels and lymphatics that form a connection with the periphery [171,172,173,174,175,176]. Beneath the dura lies the arachnoid barrier layer, composed of an outer layer of epithelial-like cells interconnected by tight junctions [177, 178]. It is this barrier that serves as a key component of the blood-CSF barrier, restricting the movement of molecules from the dura to the subarachnoid space [171, 175, 179]. The subarachnoid space plays host to vasculature networks and immune cells, with arachnoid trabeculae consisting of flattened fibroblasts-like cells connecting the arachnoid to the pia [180, 181]. CSF flows within this space and provides brain nourishment and buoyancy, as well as waste removal via venous flow and resorptive transport in the choreoid plexus [182, 183]. Tightly adhered to the brain, the pia mater is composed of a thin layer of fibroblasts, followed by a basement membrane that separates it from the underlying glia limitans. Collectively the arachnoid and pia are commonly referred to as the leptomeninges [184], within which the non-fenestrated vasculature contains tight junctions to form the leptomeningeal barrier [184,185,186,187]. Lastly, the glial limitans is constituted by astrocytic end feet processes to form a boundary between the brain parenchyma and the pia.

Meningeal lymphatic vessels (mLVs)

The presence of lymphatic vasculature within the meninges, though hinted at and often misconstrued in various anatomical accounts in the seventeenth century [188], was first visually depicted in the late eighteenth century by the anatomist Paolo Mascagni [189]. However, subsequent to this, knowledge of these lymphatic vessels lapsed into relative obscurity until the mid-twentieth century [190]. Its 'rediscovery' in modern times in both mice [173, 175] and humans [174, 176] had led to a resurgent wave of interest within the neurosciences, challenging the long-lasting dogma of the “immune-privileged” brain. Anatomically, healthy meningeal lymphatic vessels (mLVs) are found alongside dural sinuses, arteries and veins, including the superior sagittal sinus, transverse sinus, sigmoid sinus, retroglenoid vein, rostral rhinal vein, middle meningeal artery, and pterygopalatine artery [173, 175, 191,192,193,194]. Insights into the mechanistic development of lymphatic vessels is largely drawn from studies of networks in peripheral tissues. In mice, lymphatic vasculature (LV) formation is predominantly venous-derived, originating from the cardinal vein during embryogenesis. At embryonic day 9.5 (E9.5), a subpopulation of venous endothelial cells express Sox18 (a SRY-related HMG-box transcription factor), which activates prospero homeobox 1 (PROX1) [195,196,197,198]. This PROX1 activation induces specific lymphatic endothelial cell (LEC) gene expression, and inhibits blood endothelial cell-specific genes by binding to the nuclear receptors COUP-TFII [199,200,201,202]. Indeed, Prox1−/− endothelial cells fail to express LEC markers, instead retaining blood vascular endothelial properties [195], evidencing their role as a master regulator of lymphatic identity. Ultimately Sox18-PROX1 activation initiates the acquisition of LEC properties for the subsequent creation of lymph sacs and lymphatic vessel networks [203, 204]. Additional lymphangiogenic mediators include lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), which increases the expression of the platelet aggregating protein podoplanin (PDPN), in LECs at E12.5. Vascular endothelial growth factor C (VEGF-C) activation of vascular endothelial growth factor receptor-3 (VEGFR-3) is also essential for the sprouting of LVs from the embryonic veins [205, 206], allowing for the ability of LECs to migrate and form the lymphatic sacs, visible at E12.5 [207]. Buds and sprouts progress until E14.5, by which time the lymphatic development stage is completed [208, 209].

In contrast to the embryonic formation of peripheral LV, the development of the intracranial mLV occurs postnatally, in a VEGF-C dependent manner [210]. Starting at the base of the skull LEC sprouting begins at birth, postnatal P0. Temporally, lymphangiogenesis continues in a characteristic pattern alongside veins, arteries, and cranial nerves during the first weeks. The mLVs appear at the cribriform plate at P2, middle meningeal artery after P4, and grow into the transverse sinus at P8 [210]. Between P13 and P20, lymphatic vessels expand along the transverse sinus appearing at the confluence of sinuses at P16 [191, 210], before extending the length of the superior sagittal sinus toward the olfactory bulb by P20 [191]. At this time, the mLVs become functional, draining content from the CNS into the peripheral lymphatic system at the base of the skull, with the mLV network fully developed at approximately P28 [175, 191, 192, 210,211,212].

In terms of functionality, mLVs can be categorized into thin-walled “initial” lymphatic vessels, and the larger “collecting” vessels. In mice, initial lymphatic vessels are highly permeable and are located dorsally near both the transverse and superior sagittal sinus. Initial lymphatics lack smooth muscle cell (SMC) coverage, and are composed of discontinuous button-like LEC junctions [173, 175, 213]. These button-shaped junctions consist of tight junction- and adherens associated proteins, that attach adjoining LECs at the base of interdigitating flaps between cells [214,215,216]. This flap-like overlap creates mini-valves that permit the entry of interstitial fluid, macromolecules, soluble antigens and immune cells including antigen presenting cells (APCs) [215,216,217,218,219,220,221]. In contrast, collecting lymphatic vessels at the base of the skull are surrounded by SMCs to help propel fluid movement and contain tight continuous zipper-like connections and secondary intraluminal valves [217, 220]. This makes them virtually impermeable, facilitating unidirectional drainage, whilst simultaneously preventing lymphatic backflow [222, 223]. In both mice and humans, collecting meningeal lymphatic vessels extend along the jugular vein, exit the skull through various foramina, before merging with peripheral collecting lymphatics that predominantly drain into the deep cervical lymph nodes (dCLNs) [173, 174, 192, 210, 224,225,226]. On the journey between initial to collecting lymphatics, fluid transitions into specialized pre-collecting lymphatic vessels. Located at the basal foramina, they exhibit features of both initial and collecting vessels, as they lack SMC, but contain one-way valves and a mix of both button- and zipper-like junctions [192, 227]. These findings emphasize the distinct morphological characteristics of various mLV subsets, providing insight into their specialized roles in immune cell and CSF waste clearance cascades from the CNS to the periphery.

The (previously missing) link from the brain to the periphery

The 2015 multi-group discovery of mLVs in the dura mater, evidenced a role for these vessels as an initial collection site for CSF before its drainage to the dCLNs. Physically, the arachnoid barrier delineates the CSF contained in the subarachnoid space from the dura mater; however, the mechanism by which the CSF carrying waste products and immune signals from the brain reaches these mLVs in the dura was unclear. It has previously been suggested that arachnoid granulations, which are protrusions of the arachnoid mater into the venous sinuses of the dura mater, enabled drainage of CSF directly to the bloodstream [228], but tracers administrated into the CNS or CSF can drain directly to the dCLNs, demonstrating that there must be a direct route from the CSF to the dura that bypasses the bloodstream [194]. In 2024, a pioneering study identified arachnoid mater cuffs around the bridging veins that connect the subarachnoid space to the dura [229]. This finding was made by experiments that involve injecting tracers into the intracisternal magna (i.c.m) and observing their transport. The experiments revealed that the i.c.m. tracers were being transported into the dura before they had reached either the blood or the dCLNs, indicating that the drainage occurred directly from the CSF into the dura before being drained out by lymphatic vessels. This connection between the dura mater and the subarachnoid space consists of bridging veins that create discontinuities in the arachnoid barrier, forming structures termed arachnoid cuff exit (ACE) points. ACE points are present in humans and can work bi-directionally, enabling molecules and immune cells to enter from the dura mater into the brain [229]. This may explain how cytokine responses from meningeal immune cells influence brain function, a discovery that will shape the way we think about neuroinflammation in future TBI studies.

The immunological environment within the meninges

It is now recognized that the meningeal layers act as vital immunological reservoirs, hosting an array of adaptive immune cells that first arrive in development via blood vessels or calvarium bone marrow that connects the dura via specialized vascular channels [211, 230,231,232,233,234,235]. Collectively, the meningeal layers contain lymphoid cells, macrophages, mast cells, eosinophils, dendritic cells (type 1 and type 2 classical dendritic cells, plasmacytoid dendritic cells and migratory dendritic cells), neutrophils, innate lymphoid cells (ILCs), natural killer cells, plasma cells, B cells (immature and mature) and T cells (CD4, CD8 and T cell receptor gamma/delta (TCRγδ)) [186, 211, 231, 236,237,238,239,240]. Proportionally, the distribution of these cells varies across layers, with the dura largely thought to contain a higher diversity and frequency of immune cells versus the leptomeningeal layer [186]. This may be attributed to the need for tissue specific support, with the niche environment around dural sinuses containing innate lymphoid cells, macrophages, T cells, B cells and plasma cells [234, 241]. In leptomeningeal layers, macrophages, CD4, and CD8 cells, are found in large part around blood vessels in the CSF containing subarachnoid space [242,243,244,245].

Meningeal macrophages

Macrophages are heterogeneous groups of cells that carry out distinct functions depending on their location and phenotype [246]. Meningeal macrophages belong to a specialized group called border associated macrophages (BAMs), originating from yolk sac CD206+ myeloid progenitor cells [230]. In the adult, leptomeningeal BAMs can be transcriptionally delineated by CD206, Lyve1, P2rx7, and Egfl7 expression [186, 236]. In contrast, adult dural BAMs differ to their leptomeningeal counterparts as they lack Lyve-1 expression, and can be transcriptionally divided into subgroups based on major histocompatibility complex II (MHCII) expression [247, 248]. This may represent divergent roles under homeostatic or disease conditions, with MHCIIHi BAMs displaying enhanced levels of CCR2, whereas MHCIIlow BAMs contain gene signatures that include Clec4n, Clec10a and Folr2 expression [186, 211, 246, 249]. Of note, a determining factor that drives postnatal MHCII high or low differentiation, is the fms intronic regulatory element (FIRE), a highly conserved super enhancer of the colony stimulating factor 1 receptor (CSF1R) and its downstream signaling [250, 251]. This may be pertinent to consider in studies examining microglial driven inflammation in CSF1R deletion models (or via Pexidartinib (PLX) inhibition), as the effect of CSF1R in modulating facets of meningeal immunity has yet to be fully investigated. In healthy settings the functional role of BAMs is largely unknown, however evidence suggests they can act as sentinels in anti-viral defense. Following lymphocytic choriomeningitis virus infection (LCMV), BAMs become rapidly activated, acquire the viral antigen and trigger engagement by infiltrating cytotoxic T lymphocytes that are essential to resolve the infection [252]. Further, the type-1 interferon-Stat1 anti-viral pathway is induced in BAMs, blocking further LCMV infection [253]. Transcranial delivery of PLX3397 or PLX5622 to specifically deplete BAMs resulted in the death of LCMV-infected mice [253], emphasizing the importance of further investigation into BAMs in CNS disease models that contain inflammatory components within their etiology.

Border associated dendritic cells

Dendritic cells (DCs) are professional APCs that play key roles in immune surveillance in both peripheral and meningeal layers [254]. DCs in the meninges and choroid plexus arise from circulating and skull bone marrow precursor-DCs, which transform into conventional dendritic cells (cDCs) at these sites [233, 255, 256]. Investigations into their trafficking ability, revealed that peripheral DCs can migrate into the CNS across barrier sites via the C–C motif chemokine receptor 2, chemokine ligand 2 (CCR2-CCL2) signaling pathway [257]. This migration can be bi-directional, with DCs observed in the cervical and auxiliary lymph nodes 3–7 days after their injection into the CSF or brain parenchyma [258,259,260]. Meningeal mediated migratory drainage of DC occurs via initial mLVs in a CCR7 dependent manner. CCR7 is a potent receptor of DC migration toward the ligands CCL19 and CCL21, which are highly expressed by lymphatic vessels (Fig. 2). In pathological states, DCs recognize and capture antigens, upregulate CCR7 and migrate to initial mLVs before draining into the dCLNs where they can activate antigen-specific T-cell inflammatory responses [173, 225, 239, 261]. Indeed, dural and cribriform plate mLVs express CCL21, facilitating a gradient for DC migration and drainage into peripheral lymph nodes [175, 211, 225, 262]. Additionally, dural fibroblast-like cells express CCL19, providing further stimulus for CCR7 mediated signaling within the meninges; however, the role of these fibroblasts in relation to CNS lymphatic drainage is yet to be elucidated [211]. Collectively, DC populations within the meninges and CSF may contain both parenchymal infiltrating DCs as well as migratory draining DCs in transit to lymph nodes, suggesting that the holistic neuroinflammatory environment unique to specific disease states influences DC capacity, drainage and antigen presentation.

Fig. 2
figure 2

The meningeal neuroimmune interface influencing inflammatory responses in TBI. Simplified schematic of the meningeal interface in healthy and injured settings. In homeostatic conditions (left), border-associated immune cells may synergistically support brain environments through cytokine secretion (IL-4, IL-17), which can directly influence neurons. A network of initial and collecting mLVs expressing Lyve1, drain CSF solutes/molecules to the dCLNs. Immune cell drainage of dendritic and T cells into the dCLNs occurs via chemokine gradients (E.g. CCR7 expressing cells migrating towards its ligands CCL19 and CCL21). TBI (right) causes BBB breakdown and mLV dysfunction, resulting in reduced Lyve+ mLVs, and impaired drainage of solutes to the dCLNs. This TBI-induced lymphatic dysfunction and immune activation at the meningeal interface, exacerbates neuroinflammation by resident CNS cells within the brain parenchyma

Border associated T cells

The interplay between the innate CNS and adaptive immune response contributes to neuroinflammation within disease contexts. T cells are found in the meningeal space, with populations identified at dural and cribriform lymphatic sites [173, 192, 262]. Initial evidence of T cell migration into dCLNs was noted 12–48 h after their CNS injection into healthy or lesioned mice [263], with subsequent lymphatic ablation studies offering extensive characterization of T cell migration pathways via dural mLVs [225]. Mechanistically, drainage of T cells into the dCLNs via mLVs occurs in a CCR7 dependent manner [225], a process similar to that seen in inflammatory-induced peripheral T cell migration [264, 265]. Indeed, CCR7 expressing T cells are found in human CSF, most of which are thought to be central memory T cells conducting immune surveillance within the healthy subarachnoid space [266, 267]. While trafficking to dCLNs may reduce meningeal T cell pools, they are replenished by blood circulating T cells that enter the brain via the dural sinuses, and adopt tissue-resident phenotypes [211, 231]. Indeed, evidence shows elevated densities of APCs and T cells at dural sinuses, serving as an active site for APCs to acquire blood- or brain-borne pathological antigens, presenting them to local T cells [211]. Functionally, the role of a well-regulated adaptive immune response is paramount, as CD4+ and TCRγδ cells can influence CNS neuronal, glial, and homeostatic activities through cytokine secretions including IL-4, IL-17 and IFNγ [231, 268,269,270,271,272]. Furthermore, mice lacking functional T cells, and consequently deficient T cell drainage to dCLNs, have notable deficits in exploratory, social, and cognitive behaviors. [268, 273, 274]. These deficits are reversed following adoptive transfer of T cells or secondary lymphoid organ lymphocytes, further evidencing their important role in the regulation of CNS behaviors [268, 274, 275].

Border associated B cells

B cells play versatile roles within the adaptive immune response. Known predominantly for their antibody production and as precursors to antibody-producing plasma cells, they also function as APCs, and producers of proinflammatory cytokines and chemokines (reviewed in [276]). In humans, the expression of B cells and plasma cells is sparse within the CNS parenchyma [277, 278], however they are abundantly located in the meninges [277], specifically the dural layer [279]. In mice, the identification of meningeal B220+ CD11c B cells was first reported within the dural mLVs [173], with subsequent single-cell sequencing studies identifying a diverse range of progenitor, early and resident B cell populations [234, 279,280,281]. Constitutively, B cells represent ~ 15–30% of all CD45hi cells within the dural meninges, encompassing multiple stages of B cell development from pro-B to mature B cells [234, 279]. Meningeal B cells derive locally from the calvaria bone marrow niche before migrating to the meninges through specialized skull vascular channels [234]. Following this calvarial–meningeal migration, B cells complete their development locally, with factors such as CXCL12 and CXCR4 critical for their survival and differentiation [234]. IL-7 has also been implicated in supporting B cell development, alongside other niche factors in the meninges including the CNS specific antigen myelin oligodendrocyte glycoprotein [281]. For the most part, the majority of mature B cells in the CNS are naïve IgM+ cells, with small numbers of IgA+ B cells [234, 279]. In terms of migration, B cells have the capacity to drain to the dCLNs via mLV in a similar fashion to their T cell counterparts. Plasma cells (IgA+) are also found in the meninges, with a portion of this population derived from gut plasma cells [282]. This meningeal plasma cell expression is age dependent, with young mice displaying IgA+ cells, switching to an IgG+ and IgM+ plasma cell phenotype in aged mice [234].

Neuroimaging of meningeal disruption in clinical TBI

Neuroimaging provides valuable data to assist in patient evaluation and diagnosis following TBI. Common imaging modalities include conventional non-contrast computed tomography (CT) and magnetic resonance imaging (MRI), often used in the clinical work-up for injury indications in patients with GCS < 13 [283]. CT scans provide initial class I assessment of injury extent (lesion, fracture), extradural, subdural or intracranial hemorrhage, traumatic subarachnoid hemorrhage and ventricular abnormalities [284, 285]. This data is beneficial for diagnosing the mechanically induced primary trauma, yet sophisticated imaging techniques are necessary to detect subtle injuries to the brain structure and secondary injury processes. Enhanced imaging of dysregulated secondary injury cascades including glucose metabolism (functional MRI), diffuse axonal injury (diffusion tensor imaging, DTI), protein accumulation and neuroinflammation (radiotracer positron emission tomography, PET) could lead to the discovery of new imaging biomarkers and therapeutics [286].

Advancements in MRI using contrast agents (such as gadolinium) have improved the specificity of diagnostic images, allowing for identification of novel biomarkers and insights into disease progression [287, 288]. Ordinarily gadolinium is unable to cross the blood–brain barrier, and therefore acts as a surrogate for leakage of proteins and other macromolecules when detected outside of the vasculature [289]. Gadolinium post-contrast fluid-attenuated inversion recovery (FLAIR)-MRI merges a high intensity of T2 weighting with the attenuation of cerebrospinal fluid (CSF) signal. This allows for the detection of leakage of the gadolinium contrast agent across damaged barriers into the CSF space, and highlights hyperintense regions at CSF adjacent borders. This is relevant in the context of TBI, as vascular injury can occur in the parenchyma and vessels traversing the meninges [290]. Meningeal arteries and veins in the dura and subarachnoid space are particularly vulnerable to the primary impact of TBI. Indeed, recent findings suggest that Traumatic Meningeal Enhancement (TME), associated with meningeal injury and inflammation, is a novel biomarker observed by FLAIR-MRI in patients following TBI (Table 2).

Table 2 Imaging of meningeal-brain border disruption in clinical TBI

Although meningeal enhancement has been observed in neuroinflammatory contexts and in neurological disease [299,300,301], its identification in TBI is a relatively recent development (Table 2). In 2014, Roth and colleagues first reported focal enhancement of the meninges in approximately 50% of patients following a mild TBI (mTBI) [119]. A temporal follow up study identified similar TBI induced TME positive patients (50%) [293], of which 76% displayed resolution by approximately 22 days post-injury; however, 17% had persistent TME for several months (72 to 103 days post injury) [293]. This TME time course may be associated with, and influenced by, injury severity, with TME detected in moderate to severe TBI patients at 1-year post injury [296]. Collectively, these likely represent chronic inflammatory or other secondary injury cascades occurring within this compartment in the weeks, months, and years post-injury. Anatomically, TME positive mTBI patients display thick linear meningeal enhancement of the dura, including diffuse and localized convexity patterns, as well as enhancement of the falx cerebri [119, 289, 291, 292]. As the volume of data and studies expand, the diagnostic value of positive TME findings has become more apparent. TME signatures have been shown to be associated with loss of consciousness, implying clinically significant head injury [291], and FLAIR imaging protocol demonstrate superiority in detecting trauma-related abnormalities not visible on CT scans, distinguishing between acute trauma from nonspecific conditions [292]. Specifically, FLAIR protocols outperform T1W1 post-contrast sequence in identifying the presence or absence of TME, where T1W1 failed to show it in 38% of patients where it was readily shown using FLAIR [295]. To gain insights into biological mechanisms associated with TBI-induced meningeal enhancement, transcriptomic analysis from patients with TME identified 76 differentially expressed genes, including increases in IgA, FCαR, MCTP2, GPR2, and decreases in CD79A [294]. Furthermore, innate lymphoid cells (ILCs) are found in the dura and CSF of TBI patients, suggesting meningeal immune interactions [298]. Increases in VEGF2 expression in meningeal vasculature [297], suggests regenerative capacity of dural vessels; however, this finding should be repeated in subjects with clinical classification data, for meaningful translational interpretation.

Meningeal lymphatic dysfunction after TBI

Neuroinflammation, characterized by the intricate interplay between innate and adaptive immune responses, contributes to the pathophysiology of TBI (Fig. 1). A fine balance exists whereby acute activation of neuroimmune cells may be a beneficial physiological response to promote injury resolution, in contrast to aberrant neuroimmune activation that may manifest toward deleterious chronic outcomes. Identification of the immune rich lymphatic system at the meningeal barrier interface, has triggered a new area of previously unexplored research, investigating the contribution of this neuroimmune crosstalk to TBI-induced neuroinflammatory responses (Table 3) In 2020, Bolte et al. reported seminal findings evidencing the temporal series (across seven timepoints) of meningeal lymphatic disruptions in a closed head impact model of TBI. Here, they detail mLV drainage of CSF molecules to the dCLNs is impaired as early as 2 h, and persists for at least 1-month, following injury [302]. This impaired drainage was associated with changes to lymphatic vasculature, with a decrease in Lyve-1 expression observed within the first 2 to 24 h post-injury [302]. Interestingly, mLVs demonstrated a capacity for regenerative lymphangiogenesis, evidenced by the spontaneous increase of Lyve-1 coverage and complexity in meningeal whole mount preparations 1–2 weeks post injury [302]. Photothrombotic vascular damage to the dura mater and pia mater causes immediate vascular degeneration followed by revascularization at 7d post-injury [297], suggesting that changes in mLVs may occur in parallel with regenerative endothelial angiogenesis at dural sites (Fig. 2). However, across the spectrum of TBI, the extent of this naturally occurring vascular and lymphangiogenic responses varies upon injury type and severity. Lyve-1+ mLV coverage/expression is decreased at 3d (mice, impact 1.9atm) [303] and 7d (rats, impact 2.6 atm) [304] after lateral fluid percussion injury (FPI). MRI of a closed-head impact model of engineered rotational acceleration (CHIMERA) shows meningeal enhancement 7d after single and repeat injury, reflecting clinical observations [305]. Controlled cortical impact (CCI) in mice presents mixed findings: Lyve-1+ morphology is increased at 7 d (impact 1.5 mm) [306], with contrasting studies showing decreases at 3 d (impact 2 mm) [307], and 1 month (impact undisclosed) [308], highlighting the nuanced and variable nature of spontaneous lymphangiogenic responses across varied mechanisms of impact and injury parameters. Regardless, if plasticity of the lymphatic network can be induced, it may be beneficial to improve outcomes (Fig. 2). Indeed, across models of TBI, overexpression of VEGF-C drives lymphangiogenesis, enhances functional drainage and improves injury induced neurological deficits, including those seen in aged animals [303, 304, 306, 308,309,310].

Table 3 Meningeal insights in pre-clinical models of traumatic brain injury

The meningeal interface influencing TBI induced immunological responses

TBI-induced meningeal damage

The meninges host a diverse array of immune cells, as previously outlined, yet the precise details of their locations (whether in the leptomeninges or dura) and trafficking patterns in TBI still remain largely unknown. Initial studies at the meningeal interface classified the nature of damage to the barrier itself, followed by the temporal response to direct meningeal injury. Acutely, closed head meningeal compression injury (achieved by a unique skull thinning model) is characterized by rapid meningeal macrophage cell death attributed to vascular leakage and the release of reactive oxygen species [119], and also causes secondary damage to the glial limitans and brain parenchyma within the first few hours [119, 293]. The initial injury is followed by neutrophil swarming into the meninges (within 1 h), that is essential for regeneration of the initially damaged glial limitans [119]. Elevated proinflammatory cytokines IL1α/IL1β are seen in the meninges at 6 h to 1 d, as well as the chemoattractants Cxcl1 (neutrophils) and Ccl2/Ccl12 (monocytes) [293]. Over the course of a week after injury, infiltrating myeloid cells (CX3CR1lo–negCCR2hi monocytes) scavenge dead cells at the meningeal lesion core, while wound-healing macrophages (CX3CR1hiCCR2lo–negCD206+) proliferate along the lesion perimeter to promote angiogenesis through the clearance of fibrin and production of MMP-2 [293]. These studies at the level of the meninges evidenced the importance of the previously unexplored barrier immunity, setting the stage to address bi-directional interactions containing both extra-axial meningeal cascades and intra-axial brain parenchyma responses.

Modulating meningeal lymphatics in TBI

Impairment studies shed more light on how the meningeal compartments influence CNS responses, with ablation of mLVs exacerbating resident glial cell (GFAP+, IBA1+) immunoreactivity, increasing complement, reducing neuronal health markers and which collectively influenced cognitive outcomes [309]. Furthermore, administration of the pro-lymphangiogenic VEGF-C to aged mice reduced brain gliosis and improved cognition. Integrating adaptive immunity, TBI induces the accumulation of Granzyme B+ CD8+ cytotoxic T cells, a response preceded by increases in IL-17-producing CD4+ T cells and IFNγ-producing CD4+ T cells [311]. This sequence is significant, given Th17 cell responses through IL-17 and IL-21, can enhance the cytotoxic capability of CD8+ T cells [311]. In K14-VEGFR3-Ig (TG) mice that have defective growth and lack mLVs alongside sclerotic dCLNs, a reduction in the perilesional infiltration of T-cells is observed [312]. Specifically, TBI-K14-VEGFR3-Ig mice show reduced levels of infiltrating CD4+ T cells, suggesting that trauma induced brain-derived antigens may be partially drained through the mLVs to the dCLNs to elicit Th-2 mediated responses [312]. Indeed, lymphatic vessels and LECs themselves play a direct chemoattractant role in the maturation of T cells, turning naive T cells into a memory-like subset of quiescent yet antigen-experienced CD8+ cells that can rapidly differentiate into an effector upon inflammatory antigenic challenge [313]. Dendritic antigen presenting cells can also survey the inflammatory CNS milieu, traverse the mLVs in a CCR7, CCL19 and CCL21 manner, and interact with T cells in the dCLNs. During trauma, DCs are elevated and influence post-injury immune responses [129, 259, 314, 315], yet this meningeal migration of DCs downstream activation of adaptive immune responses hasn’t been studied in the context of TBI.

Insights from transcriptomic approaches

In order to gain a greater understanding of the cell specific responses that occur in the meninges after TBI, we and others have taken a transcriptomic approach [184, 302, 316, 317]. scRNA-seq shows increased meningeal macrophages, CD8+T cells, T helper cells Th2 and Th17, immature-mature B cells, dendritic cells, and fibroblasts in meningeal compartments at 1-week post injury [302]. Similarly, we identified time dependent alterations in the meningeal transcriptome. T-cells respond acutely, followed by chronic B-cell and immunoglobulin production in an age dependent manner, which may be regulated by upstream Type-1 IFNs, Ccr2 and IL-33 interactions [317]. Supporting this, meningeal macrophages display strong type-1 IFN signatures (elevated IFNβ and IRF5) and sub cluster into “inflammatory” and “resolution” classes [302]. Resolution macrophages express of antigen presentation-related genes (H2-Eb1, H2-Ab1, H2-Aa, Cd74) and anti-inflammatory genes Stab1, Nrros, and Dab2 which are involved in suppression of type I IFN responses. Conversely, meningeal inflammatory macrophages are defined by their expression of Ccr2 and chemotaxis genes Ccr7, Ccl22, and Ccl5.

Future avenues for neuroimmune investigation

These seminal pre-clinical studies of the meningeal response after TBI prompt numerous inquiries for future investigation within the field of neurotrauma. Not only do the meninges harbor immune cells that contribute to a vast array of responses, the mLVs play a crucial role as the waste-removal system in draining CSF, ISF, and CNS-derived molecules from the brain parenchyma to the dCLNs. The effect of their damage caused by primary injury and how that influences removal of proteins such as Aβ and tau remain to be characterized. Additionally, stratification of the level of damage to the LVs, subsequent lymphangiogenic recovery, and the effect on the flow of CSF throughout the brain is still to be characterized. Transcriptomic studies suggest inflammatory molecules may regulate meningeal derived inflammatory responses, particularly chemokines. Indeed, modulation of the CCR2-CCL2 signaling axis in TBI has been shown to be beneficial [77, 318,319,320]. CCL2−/− mice show delayed reductions in lesion size beginning at 28 days post injury. It might be postulated that this delayed response may be due to deficiency in meningeal mLV acutely, prior to lymphangiogenic recovery, in combination with altered CCL2 chronic immune responses. Indeed, CCR2−/− mice show altered monocyte/macrophage influx and reduced crosstalk with innate cells, inhibiting the generation of type-1 IFN microglial responses after TBI, with pharmacological blockade of CCR2 improving cognitive outcomes at 28-day timepoints [318, 319]. Populations of macrophages after TBI were Mrc1+ Lyve1+ [319] suggesting microglial cross communication between meningeal cells, and as of now investigations into TBI mediated CCR2-CCL2 axis at the mLV immune interface are yet to be conducted, potentially warranting future investigation.

Alongside CCL2, CCL7 has been observed in the meninges single TBI [316]. CCR7 is expressed in a variety of peripheral immune cells including DCs and T-cells. Given CCR7+ immune cells migrate to the dCLNs via a CCL19 and CCL21 chemokine gradient (Brandum et al., 2021), suggests the potential DCs (that have phagocytosed TBI-induced antigens) and naïve T-cells migrate into LVs and dCLNs and present antigens to naïve CD8+ T-cells and CD4+ T-cells and activate them in response to TBI. Future studies investigating this potential using agonists/antagonists or conditional CCR7Ko models may be of interest to examine pathway influences neuroimmune outcomes and cognition in TBI, similar to that observed in 5xFAD models [239]. Most importantly, these questions may be influenced by factors like age, sex, and injury severity. Future studies should incorporate these variables to stratify the immune response at the meningeal interface following traumatic brain injury (TBI).

Conclusions

TBI introduces a complex interplay between neuroinflammatory responses and immune dysregulation. We now understand that the meninges play a role in modulating this neuroinflammatory response, serving as the interface between the brain and the immune system; however, we still do not fully understand the mechanisms underlying prolonged neuroinflammation or how the temporal progression of damage to the meningeal lymphatic vessels influences cell trafficking and resolution. After TBI, immune cells (monocytes, macrophages, neutrophils) are available at the meningeal interface to immediately influence the brain, and infiltrating cells such as T and B cells can still be found in the brain and meningeal interface months following the injury. Does the presence of meningeal immune cells and the soluble factors released in response to trauma signal to, and amplify, the innate microglial responses? Are these cells being constantly trafficked into the brain, attracted by continuous damage signals? Do invading immune cells enter the CNS to mediate damage, but are unable to exit due to trauma-induced mLV dysfunction? Targeting the ability of immune cells to enter the CNS in response to injury, enhancing their ability to drain from the CNS, and gaining a better understanding of the crosstalk between the brain, meninges, and dCLN will allow us to harness the power of the immune system to enhance recovery from TBI.

Availability of data and materials

All data generated or analyzed during this manuscript are included in this article.

Abbreviations

ACE:

Arachnoid cuff exit

APC:

Antigen-presenting cells

AQP4:

Aquaporin-4

Arg:

Arginase

ASC:

Protein apoptosis associated speck-like protein

b2M:

Beta-2-microglobuli

BAMs:

Border associated macrophages

BBB:

Blood brain barrier

BDNF:

Brain-derived neurotrophic factor

C3:

Complement component 3

CCI:

Controlled cortical impact

CCL:

C-C motif ligand

CCR:

C-C chemokine receptor.

CCR2-CCL2:

Chemokine receptor 2, chemokine ligand 2

CD:

Cluster of differentiation

cDCs:

Conventional dendritic cells

CHIMERA:

Closed-head impact model of engineered rotational acceleration

COX:

Cyclooxygenase

CR:

Complement receptor

CRP:

C-reactive protein

CSF:

Cerebrospinal fluid

CSF1R:

Colony stimulating factor 1 receptor

CT:

Computed tomography

CXCL8:

C-X-C motif chemokine ligand

DAMPS:

Damage-associated molecular patterns

DC:

Dendritic cells

dCLNs:

Deep cervical lymph nodes

DEGs:

Differentially expressed genes

DNAM:

DNAX accessory molecule

ECSAS:

Extravasation of contrast into the subarachnoid space

FBG:

Fibrinogen

FIRE:

Fms intronic regulatory element

FITC:

Fluorescein isothiocyanate

FLAIR:

Fluid-attenuated inversion recovery

FPI:

Fluid percussion injury

GCS:

Glasgow Coma Scale

GFAP:

Glial fibrillary acidic protein

HARM:

Hyperintense acute reperfusion marker

HLA:

Human leukocyte antigen

HMGB1:

High mobility group box 1

HSP:

Heat-shock protein

i.c.m.:

Intracisternal magna

i.v.:

Intravenous

ICAM:

Intracellular adhesion molecule

IFN:

Interferon

IgG:

Immunoglobulin G

IL:

Interleukin

ILCs:

Innate lymphoid cells

iNOS:

Inducible nitric oxide synthase

IQR:

Interquartile range

KIR:

Killer-cell immunoglobulin-like receptors

LCMV:

Lymphocytic choriomeningitis virus infection

LEC:

Lymphatic endothelial cell

LV:

Lymphatic vasculature

LYVE-1:

Lymphatic vessel endothelial hyaluronan receptor 1

MCP:

Monocyte chemoattractant protein

ME:

Meningeal enhancement

MHCII:

Major histocompatibility complex II

mLVs:

Meningeal lymphatic vessels

MMP:

Matrix metalloproteinases

MPO:

Myeloperoxidase

MRI:

Magnetic resonance imaging

MRP:

Macrophage-related protein

mTBI:

Mild traumatic brain injury

Myd88:

Myeloid differentiation primary response 88

NADPH:

Nicotinamide adenine dinucleotide phosphate

NLRP1:

NLR Family Pyrin Domain Containing 1

NF-κB:

Nuclear factor kappa B

NK:

Natural killer

NOX:

NADPH oxidase

NT:

Neurotrophin

PDPN:

Platelet aggregating protein podoplanin

PK:

Ligand [11C](R)PK11195

PLX:

Pexidartinib

PROX1:

Prospero homeobox 1

PRR:

Pattern recognition receptors

RAGE:

Receptor for advanced glycation end-products

S100B:

S100 calcium-binding protein B

sIL:

Soluble interleukin receptor

SMC:

Smooth muscle cell

TAM:

Trauma Associated Microglia

TBI:

Traumatic Brain Injury

TCRγδ:

T cell receptor gamma/delta

TGF:

Transforming growth factor

THINC:

Traumatic Head Injury Neuroimaging Classification study (NCT01132937)

TLRs:

Toll like receptors

TME:

Traumatic Meningeal Enhancement

TMEM:

Transmembrane protein

TNF:

Tumor necrosis factor

T-reg:

Regulatory T cells

UCH-L1:

Ubiquitin carboxyl-terminal hydrolase isozyme L1

VEGF-C:

Vascular endothelial growth factor C

VEGFR-3:

Vascular endothelial growth factor receptor-3

ZO:

Zonula Occludens

References

  1. Injury, G.B.D.T.B. and C. Spinal Cord Injury, Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol, 2019. 18(1): p. 56–87.

  2. Dewan MC, et al. Estimating the global incidence of traumatic brain injury. J Neurosurg. 2018;130(4):1080–97.

    Article  PubMed  Google Scholar 

  3. Peterson AB, Xu L, Daughtery J, Breiding MJ. Surveillance report of traumatic brain injury-related emergency department visits, hospitalizations, and deaths, United States, 2014. United States, 2019.

  4. Faul MW, Marlena M, Xu L, Coronado VG, Marlena M, Xu Likang, Coronado VG. Traumatic brain injury in the United States. Atlanta, GA: national Center for injury Prevention and Control, Centers for disease Control and Prevention. 2010.

  5. Gardner RC, et al. Geriatric traumatic brain injury: epidemiology, outcomes, knowledge gaps, and future directions. J Neurotrauma. 2018;35(7):889–906.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Papa L, Mendes ME, Braga CF. Mild traumatic brain injury among the geriatric population. Cur Transl Geriatr Exp Gerontol Rep. 2012;1:135–42.

    Article  Google Scholar 

  7. Susman M, et al. Traumatic brain injury in the elderly: increased mortality and worse functional outcome at discharge despite lower injury severity. J Trauma Acute Care Surg. 2002;53(2):219–24.

    Article  Google Scholar 

  8. Green RE, et al. Examining moderators of cognitive recovery trajectories after moderate to severe traumatic brain injury. Arch Phys Med Rehabil. 2008;89(12 Suppl):S16-24.

    Article  PubMed  Google Scholar 

  9. McIntyre A, et al. Mortality among older adults after a traumatic brain injury: a meta-analysis. Brain Inj. 2013;27(1):31–40.

    Article  PubMed  Google Scholar 

  10. Thompson HJ, McCormick WC, Kagan SH. Traumatic brain injury in older adults: epidemiology, outcomes, and future implications. J Am Geriatr Soc. 2006;54(10):1590–5.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Testa JA, et al. Outcome after traumatic brain injury: effects of aging on recovery. Arch Phys Med Rehabil. 2005;86(9):1815–23.

    Article  PubMed  Google Scholar 

  12. CDC. TBI Data and Statistics 2021; https://www.cdc.gov/traumaticbraininjury/data/index.html.

  13. Saatman KE, et al. Classification of traumatic brain injury for targeted therapies. J Neurotrauma. 2008;25(7):719–38.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Simon DW, et al. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol. 2017;13(3):171–91.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Graham NS, Sharp DJ. Understanding neurodegeneration after traumatic brain injury: from mechanisms to clinical trials in dementia. J Neurol Neurosurg Psychiatry. 2019;90(11):1221–33.

    Article  PubMed  Google Scholar 

  16. Roh JS, Sohn DH. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 2018;18(4): e27.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Rai V, Mathews G, Agrawal DK. Translational and clinical significance of DAMPs, PAMPs, and PRRs in trauma-induced inflammation. Arch Clin Biomed Res. 2022;6(5):673–85.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rodriguez-Baeza A, et al. Morphological features in human cortical brain microvessels after head injury: a three-dimensional and immunocytochemical study. Anat Rec A Discov Mol Cell Evol Biol. 2003;273(1):583–93.

    Article  PubMed  Google Scholar 

  19. Hay JR, et al. Blood-brain barrier disruption is an early event that may persist for many years after traumatic brain injury in humans. J Neuropathol Exp Neurol. 2015;74(12):1147–57.

    CAS  PubMed  Google Scholar 

  20. Blyth BJ, et al. Validation of serum markers for blood-brain barrier disruption in traumatic brain injury. J Neurotrauma. 2009;26(9):1497–507.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ho KM, et al. Prognostic significance of blood-brain barrier disruption in patients with severe nonpenetrating traumatic brain injury requiring decompressive craniectomy. J Neurosurg. 2014;121(3):674–9.

    Article  PubMed  Google Scholar 

  22. Saw MM, et al. Differential disruption of blood-brain barrier in severe traumatic brain injury. Neurocrit Care. 2014;20(2):209–16.

    Article  CAS  PubMed  Google Scholar 

  23. Stahel PF, et al. Intrathecal levels of complement-derived soluble membrane attack complex (sC5b-9) correlate with blood-brain barrier dysfunction in patients with traumatic brain injury. J Neurotrauma. 2001;18(8):773–81.

    Article  CAS  PubMed  Google Scholar 

  24. Csuka E, et al. IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-α, TGF-β1 and blood–brain barrier function. J Neuroimmunol. 1999;101(2):211–21.

    Article  CAS  PubMed  Google Scholar 

  25. Tomkins O, et al. Blood-brain barrier breakdown following traumatic brain injury: a possible role in posttraumatic epilepsy. Cardiovasc Psychiatry Neurol. 2011;2011: 765923.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Johnson VE, et al. Mechanical disruption of the blood-brain barrier following experimental concussion. Acta Neuropathol. 2018;135(5):711–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Blyth BJ, et al. Elevated serum ubiquitin carboxy-terminal hydrolase L1 is associated with abnormal blood-brain barrier function after traumatic brain injury. J Neurotrauma. 2011;28(12):2453–62.

    Article  PubMed  Google Scholar 

  28. Roberts DJ, et al. A prospective evaluation of the temporal matrix metalloproteinase response after severe traumatic brain injury in humans. J Neurotrauma. 2013;30(20):1717–26.

    Article  PubMed  Google Scholar 

  29. Kossmann T, et al. Elevated levels of the complement components C3 and factor B in ventricular cerebrospinal fluid of patients with traumatic brain injury. J Neuroimmunol. 1997;73(1–2):63–9.

    Article  CAS  PubMed  Google Scholar 

  30. Au AK, et al. Cerebrospinal fluid levels of high-mobility group box 1 and cytochrome C predict outcome after pediatric traumatic brain injury. J Neurotrauma. 2012;29(11):2013–21.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Laird MD, et al. High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4. Glia. 2014;62(1):26–38.

    Article  PubMed  Google Scholar 

  32. Gao TL, et al. Expression of HMGB1 and RAGE in rat and human brains after traumatic brain injury. J Trauma Acute Care Surg. 2012;72(3):643–9.

    Article  CAS  PubMed  Google Scholar 

  33. Adamczak SE, et al. Pyroptotic neuronal cell death mediated by the AIM2 inflammasome. J Cereb Blood Flow Metab. 2014;34(4):621–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Adamczak S, et al. Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article. J Neurosurg. 2012;117(6):1119–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Seshadri A, et al. Phenotyping the immune response to trauma: a multiparametric systems immunology approach. Crit Care Med. 2017;45(9):1523–30.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ryan E, et al. Mild-to-severe traumatic brain injury in children: altered cytokines reflect severity. J Neuroinflamm. 2022;19(1):36.

    Article  CAS  Google Scholar 

  37. Chaban V, et al. Systemic inflammation persists the first year after mild traumatic brain injury: results from the prospective trondheim mild traumatic brain injury study. J Neurotrauma. 2020;37(19):2120–30.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Kossmann T, et al. Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production. J Cereb Blood Flow Metab. 1997;17(3):280–9.

    Article  CAS  PubMed  Google Scholar 

  39. Shiozaki T, et al. Cerebrospinal fluid concentrations of anti-inflammatory mediators in early-phase severe traumatic brain injury. Shock. 2005;23(5):406–10.

    Article  CAS  PubMed  Google Scholar 

  40. Juengst SB, et al. Exploratory associations with tumor necrosis factor-alpha, disinhibition and suicidal endorsement after traumatic brain injury. Brain Behav Immun. 2014;41:134–43.

    Article  CAS  PubMed  Google Scholar 

  41. Hayakata T, et al. Changes in CSF S100B and cytokine concentrations in early-phase severe traumatic brain injury. Shock. 2004;22(2):102–7.

    Article  CAS  PubMed  Google Scholar 

  42. Maier B, et al. Delayed elevation of soluble tumor necrosis factor receptors p75 and p55 in cerebrospinal fluid and plasma after traumatic brain injury. Shock. 2006;26(2):122–7.

    Article  CAS  PubMed  Google Scholar 

  43. Ross SA, et al. The presence of tumour necrosis factor in CSF and plasma after severe head injury. Br J Neurosurg. 1994;8(4):419–25.

    Article  CAS  PubMed  Google Scholar 

  44. Yan EB, et al. Post-traumatic hypoxia is associated with prolonged cerebral cytokine production, higher serum biomarker levels, and poor outcome in patients with severe traumatic brain injury. J Neurotrauma. 2014;31(7):618–29.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Waters RJ, et al. Cytokine gene polymorphisms and outcome after traumatic brain injury. J Neurotrauma. 2013;30(20):1710–6.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Helmy A, et al. The cytokine response to human traumatic brain injury: temporal profiles and evidence for cerebral parenchymal production. J Cereb Blood Flow Metab. 2011;31(2):658–70.

    Article  CAS  PubMed  Google Scholar 

  47. Liao Y, et al. Oxidative burst of circulating neutrophils following traumatic brain injury in human. PLoS ONE. 2013;8(7): e68963.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Di Battista AP, et al. Inflammatory cytokine and chemokine profiles are associated with patient outcome and the hyperadrenergic state following acute brain injury. J Neuroinflammation. 2016;13:40.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Devoto C, et al. Inflammation relates to chronic behavioral and neurological symptoms in military personnel with traumatic brain injuries. Cell Transplant. 2017;26(7):1169–77.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ferreira LCB, et al. Increased levels of interleukin-6, -8 and -10 are associated with fatal outcome following severe traumatic brain injury. Brain Inj. 2014;28(10):1311–6.

    Article  PubMed  Google Scholar 

  51. Buttram SD, et al. Multiplex assessment of cytokine and chemokine levels in cerebrospinal fluid following severe pediatric traumatic brain injury: effects of moderate hypothermia. J Neurotrauma. 2007;24(11):1707–17.

    Article  PubMed  Google Scholar 

  52. Chiaretti A, et al. Interleukin 1beta and interleukin 6 relationship with paediatric head trauma severity and outcome. Childs Nerv Syst. 2005;21(3):185–93 (discussion 194).

    Article  PubMed  Google Scholar 

  53. Hadjigeorgiou GM, et al. IL-1RN and IL-1B gene polymorphisms and cerebral hemorrhagic events after traumatic brain injury. Neurology. 2005;65(7):1077–82.

    Article  CAS  PubMed  Google Scholar 

  54. Helmy A, et al. Principal component analysis of the cytokine and chemokine response to human traumatic brain injury. PLoS ONE. 2012;7(6): e39677.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mellergard P, et al. Differences in cerebral extracellular response of interleukin-1beta, interleukin-6, and interleukin-10 after subarachnoid hemorrhage or severe head trauma in humans. Neurosurgery. 2011;68(1):12–9 (discussion 19).

    Article  PubMed  Google Scholar 

  56. Perez-Barcena J, et al. Lack of correlation among intracerebral cytokines, intracranial pressure, and brain tissue oxygenation in patients with traumatic brain injury and diffuse lesions. Crit Care Med. 2011;39(3):533–40.

    Article  CAS  PubMed  Google Scholar 

  57. Hutchinson PJ, et al. Inflammation in human brain injury: intracerebral concentrations of IL-1alpha, IL-1beta, and their endogenous inhibitor IL-1ra. J Neurotrauma. 2007;24(10):1545–57.

    Article  PubMed  Google Scholar 

  58. Sun Y, et al. Elevated serum levels of inflammation-related cytokines in mild traumatic brain injury are associated with cognitive performance. Front Neurol. 2019;10:1120.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Zhao P, et al. Sex differences in cerebral blood flow and serum inflammatory cytokines and their relationships in mild traumatic brain injury. Front Neurol. 2021;12: 755152.

    Article  PubMed  Google Scholar 

  60. Bell MJ, et al. Interleukin-6 and interleukin-10 in cerebrospinal fluid after severe traumatic brain injury in children. J Neurotrauma. 1997;14(7):451–7.

    Article  CAS  PubMed  Google Scholar 

  61. Kossmann T, et al. Interleukin-6 released in human cerebrospinal fluid following traumatic brain injury may trigger nerve growth factor production in astrocytes. Brain Res. 1996;713(1–2):143–52.

    Article  CAS  PubMed  Google Scholar 

  62. Kossmann T, et al. Intrathecal and serum interleukin-6 and the acute-phase response in patients with severe traumatic brain injuries. Shock. 1995;4(5):311–7.

    Article  CAS  PubMed  Google Scholar 

  63. Maier B, et al. Differential release of interleukines 6, 8, and 10 in cerebrospinal fluid and plasma after traumatic brain injury. Shock. 2001;15(6):421–6.

    Article  CAS  PubMed  Google Scholar 

  64. Shore PM, et al. Continuous versus intermittent cerebrospinal fluid drainage after severe traumatic brain injury in children: effect on biochemical markers. J Neurotrauma. 2004;21(9):1113–22.

    Article  PubMed  Google Scholar 

  65. Singhal A, et al. Association between cerebrospinal fluid interleukin-6 concentrations and outcome after severe human traumatic brain injury. J Neurotrauma. 2002;19(8):929–37.

    Article  CAS  PubMed  Google Scholar 

  66. Winter CD, et al. Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury. Brain. 2004;127(Pt 2):315–20.

    Article  PubMed  Google Scholar 

  67. Vedantam A, et al. Early versus late profiles of inflammatory cytokines after mild traumatic brain injury and their association with neuropsychological outcomes. J Neurotrauma. 2021;38(1):53–62.

    Article  PubMed  Google Scholar 

  68. Magatti M, et al. Systemic immune response in young and elderly patients after traumatic brain injury. Immun Ageing. 2023;20(1):41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Nwachuku EL, et al. Time course of cerebrospinal fluid inflammatory biomarkers and relationship to 6-month neurologic outcome in adult severe traumatic brain injury. Clin Neurol Neurosurg. 2016;149:1–5.

    Article  PubMed  Google Scholar 

  70. Frugier T, et al. In situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury. J Neurotrauma. 2010;27(3):497–507.

    Article  PubMed  Google Scholar 

  71. Gill J, et al. Higher exosomal tau, amyloid-beta 42 and IL-10 are associated with mild TBIs and chronic symptoms in military personnel. Brain Inj. 2018;32(10):1277–84.

    PubMed  PubMed Central  Google Scholar 

  72. Kirchhoff C, et al. Cerebrospinal IL-10 concentration is elevated in non-survivors as compared to survivors after severe traumatic brain injury. Eur J Med Res. 2008;13(10):464–8.

    CAS  PubMed  Google Scholar 

  73. Schneider Soares FM, et al. Interleukin-10 is an independent biomarker of severe traumatic brain injury prognosis. NeuroImmunoModulation. 2012;19(6):377–85.

    Article  PubMed  Google Scholar 

  74. Tylicka M, et al. BDNF and IL-8, but not UCHL-1 and IL-11, are markers of brain injury in children caused by mild head trauma. Brain Sci. 2020;10(10):665.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Morganti-Kossmann MC, et al. TGF-beta is elevated in the CSF of patients with severe traumatic brain injuries and parallels blood-brain barrier function. J Neurotrauma. 1999;16(7):617–28.

    Article  CAS  PubMed  Google Scholar 

  76. Li Z, et al. M-CSF, IL-6, and TGF-beta promote generation of a new subset of tissue repair macrophage for traumatic brain injury recovery. Sci Adv. 2021. https://doi.org/10.1126/sciadv.abb6260.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Semple BD, et al. Role of CCL2 (MCP-1) in traumatic brain injury (TBI): evidence from severe TBI patients and CCL2-/- mice. J Cereb Blood Flow Metab. 2010;30(4):769–82.

    Article  PubMed  Google Scholar 

  78. Stefini R, et al. Chemokine detection in the cerebral tissue of patients with posttraumatic brain contusions. J Neurosurg. 2008;108(5):958–62.

    Article  CAS  PubMed  Google Scholar 

  79. Whalen MJ, et al. Interleukin-8 is increased in cerebrospinal fluid of children with severe head injury. Crit Care Med. 2000;28(4):929–34.

    Article  CAS  PubMed  Google Scholar 

  80. Yatsiv I, et al. Elevated intracranial IL-18 in humans and mice after traumatic brain injury and evidence of neuroprotective effects of IL-18-binding protein after experimental closed head injury. J Cereb Blood Flow Metab. 2002;22(8):971–8.

    Article  CAS  PubMed  Google Scholar 

  81. Lenzlinger PM, et al. Markers for cell-mediated immune response are elevated in cerebrospinal fluid and serum after severe traumatic brain injury in humans. J Neurotrauma. 2001;18(5):479–89.

    Article  CAS  PubMed  Google Scholar 

  82. Li Z, et al. Expression and clinical significance of non-phagocytic cell oxidase 2 and 4 after human traumatic brain injury. Neurol Sci. 2015;36(1):61–71.

    Article  PubMed  Google Scholar 

  83. Holmin S, et al. Intracerebral inflammation after human brain contusion. Neurosurgery. 1998;42(2):291–8 (discussion 298-9).

    Article  CAS  PubMed  Google Scholar 

  84. Beschorner R, et al. CD14 expression by activated parenchymal microglia/macrophages and infiltrating monocytes following human traumatic brain injury. Acta Neuropathol. 2002;103(6):541–9.

    Article  CAS  PubMed  Google Scholar 

  85. Engel S, et al. Dynamics of microglial activation after human traumatic brain injury are revealed by delayed expression of macrophage-related proteins MRP8 and MRP14. Acta Neuropathol. 2000;100(3):313–22.

    Article  CAS  PubMed  Google Scholar 

  86. Soares HD, et al. Inflammatory leukocytic recruitment and diffuse neuronal degeneration are separate pathological processes resulting from traumatic brain injury. J Neurosci. 1995;15(12):8223–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hicks RR, et al. Alterations in BDNF and NT-3 mRNAs in rat hippocampus after experimental brain trauma. Brain Res Mol Brain Res. 1997;48(2):401–6.

    Article  CAS  PubMed  Google Scholar 

  88. Carlos TM, et al. Expression of endothelial adhesion molecules and recruitment of neutrophils after traumatic brain injury in rats. J Leukoc Biol. 1997;61(3):279–85.

    Article  CAS  PubMed  Google Scholar 

  89. Ebert SE, et al. Molecular imaging of neuroinflammation in patients after mild traumatic brain injury: a longitudinal (123) I-CLINDE single photon emission computed tomography study. Eur J Neurol. 2019;26(12):1426–32.

    Article  CAS  PubMed  Google Scholar 

  90. Ramlackhansingh AF, et al. Inflammation after trauma: microglial activation and traumatic brain injury. Ann Neurol. 2011;70(3):374–83.

    Article  PubMed  Google Scholar 

  91. Johnson VE, et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain. 2013;136(Pt 1):28–42.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Oehmichen M, Theuerkauf I, Meissner C. Is traumatic axonal injury (AI) associated with an early microglial activation? Application of a double-labeling technique for simultaneous detection of microglia and AI. Acta Neuropathol. 1999;97(5):491–4.

    Article  CAS  PubMed  Google Scholar 

  93. Schwab JM, et al. Persistent accumulation of cyclooxygenase-1-expressing microglial cells and macrophages and transient upregulation by endothelium in human brain injury. J Neurosurg. 2002;96(5):892–9.

    Article  CAS  PubMed  Google Scholar 

  94. Bohnert S, et al. TMEM119 as a specific marker of microglia reaction in traumatic brain injury in postmortem examination. Int J Legal Med. 2020;134(6):2167–76.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Zhang D, et al. TLR4 inhibitor resatorvid provides neuroprotection in experimental traumatic brain injury: implication in the treatment of human brain injury. Neurochem Int. 2014;75:11–8.

    Article  CAS  PubMed  Google Scholar 

  96. Li W, et al. Enhanced cortical expression of myeloid differentiation primary response protein 88 (Myd88) in patients with traumatic brain injury. J Surg Res. 2013;180(1):133–9.

    Article  CAS  PubMed  Google Scholar 

  97. Roquilly A, et al. Role of IL-12 in overcoming the low responsiveness of NK cells to missing self after traumatic brain injury. Clin Immunol. 2017;177:87–94.

    Article  CAS  PubMed  Google Scholar 

  98. Mrakovcic-Sutic I, et al. Early changes in frequency of peripheral blood lymphocyte subpopulations in severe traumatic brain-injured patients. Scand J Immunol. 2010;72(1):57–65.

    Article  CAS  PubMed  Google Scholar 

  99. Kong XD, et al. Alterations of natural killer cells in traumatic brain injury. Neurosci Bull. 2014;30(6):903–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Li M, et al. Role of regulatory T cell in clinical outcome of traumatic brain injury. Chin Med J. 2015;128(8):1072–8.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Gao W, et al. Adrenomedullin reduces secondary injury and improves outcome in rats with fluid percussion brain injury. World Neurosurg. 2018;119:e765–73.

    Article  PubMed  Google Scholar 

  102. Jiang Z, et al. Catechin attenuates traumatic brain injury-induced blood–brain barrier damage and improves longer-term neurological outcomes in rats. Exp Physiol. 2017;102(10):1269–77.

    Article  CAS  PubMed  Google Scholar 

  103. Alluri H, et al. Attenuation of blood-brain barrier breakdown and hyperpermeability by calpain inhibition. J Biol Chem. 2016;291(53):26958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Main BS, et al. Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury. Mol Neurodegener. 2018;13(1):17.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Shigemori Y. et al. Matrix metalloproteinase-9 is associated with blood-brain barrier opening and brain edema formation after cortical contusion in rats. in Brain Edema XIII. 2006. Springer.

  106. Nag S, Venugopalan R, Stewart DJ. Increased caveolin-1 expression precedes decreased expression of occludin and claudin-5 during blood-brain barrier breakdown. Acta Neuropathol. 2007;114(5):459–69.

    Article  CAS  PubMed  Google Scholar 

  107. Wang Z-G, et al. bFGF Protects against blood-brain barrier damage through junction protein regulation via PI3K-Akt-Rac1 pathway following traumatic brain injury. Mol Neurobiol. 2016;53(10):7298–311.

    Article  CAS  PubMed  Google Scholar 

  108. Dore-Duffy P, et al. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res. 2000;60(1):55–69.

    Article  CAS  PubMed  Google Scholar 

  109. Needham EJ, et al. The immunological response to traumatic brain injury. J Neuroimmunol. 2019;332:112–25.

    Article  CAS  PubMed  Google Scholar 

  110. Alam A, et al. Cellular infiltration in traumatic brain injury. J Neuroinflamm. 2020;17(1):328.

    Article  CAS  Google Scholar 

  111. Lawson LJ, et al. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience. 1990;39(1):151–70.

    Article  CAS  PubMed  Google Scholar 

  112. Hayes GM, Woodroofe MN, Cuzner ML. Microglia are the major cell type expressing MHC class II in human white matter. J Neurol Sci. 1987;80(1):25–37.

    Article  CAS  PubMed  Google Scholar 

  113. Paolicelli RC, et al. Microglia states and nomenclature: a field at its crossroads. Neuron. 2022;110(21):3458–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Blinzinger K, Kreutzberg G. Displacement of synaptic terminals from regenerating motoneurons by microglial cells. Z Zellforsch Mikrosk Anat. 1968;85(2):145–57.

    Article  CAS  PubMed  Google Scholar 

  115. Hickman SE, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci. 2013;16(12):1896–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Cserép C, et al. Microglia monitor and protect neuronal function through specialized somatic purinergic junctions. Science. 2020;367(6477):528–37.

    Article  PubMed  Google Scholar 

  117. Loane DJ, et al. Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J Neuropathol Exp Neurol. 2014;73(1):14–29.

    Article  CAS  PubMed  Google Scholar 

  118. Davalos D, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8(6):752–8.

    Article  CAS  PubMed  Google Scholar 

  119. Roth TL, et al. Transcranial amelioration of inflammation and cell death after brain injury. Nature. 2014;505(7482):223–8.

    Article  CAS  PubMed  Google Scholar 

  120. Wang G, et al. Microglia/macrophage polarization dynamics in white matter after traumatic brain injury. J Cereb Blood Flow Metab. 2013;33(12):1864–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Turtzo LC, et al. Macrophagic and microglial responses after focal traumatic brain injury in the female rat. J Neuroinflammation. 2014;11:82.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Shen H, et al. Microglia and astrocytes mediate synapse engulfment in a MER tyrosine kinase-dependent manner after traumatic brain injury. Neural Regen Res. 2023;18(8):1770–6.

    CAS  PubMed  Google Scholar 

  123. Krukowski K, et al. Novel microglia-mediated mechanisms underlying synaptic loss and cognitive impairment after traumatic brain injury. Brain Behav Immun. 2021;98:122–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ritzel RM, et al. Sustained neuronal and microglial alterations are associated with diverse neurobehavioral dysfunction long after experimental brain injury. Neurobiol Dis. 2020;136: 104713.

    Article  CAS  PubMed  Google Scholar 

  125. Cao T, et al. Morphological and genetic activation of microglia after diffuse traumatic brain injury in the rat. Neuroscience. 2012;225:65–75.

    Article  CAS  PubMed  Google Scholar 

  126. Robinson S, et al. Microstructural and microglial changes after repetitive mild traumatic brain injury in mice. J Neurosci Res. 2017;95(4):1025–35.

    Article  CAS  PubMed  Google Scholar 

  127. Witcher KG, et al. Traumatic brain injury causes chronic cortical inflammation and neuronal dysfunction mediated by microglia. J Neurosci. 2021;41(7):1597–616.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Izzy S, et al. Time-dependent changes in microglia transcriptional networks following traumatic brain injury. Front Cell Neurosci. 2019;13:307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Jin X, et al. Temporal changes in cell marker expression and cellular infiltration in a controlled cortical impact model in adult male C57BL/6 mice. PLoS ONE. 2012;7(7): e41892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308(5726):1314–8.

    Article  CAS  PubMed  Google Scholar 

  131. Zhang Z, et al. Immunolocalization of Toll-like receptors 2 and 4 as well as their endogenous ligand, heat shock protein 70, in rat traumatic brain injury. NeuroImmunoModulation. 2012;19(1):10–9.

    Article  PubMed  Google Scholar 

  132. Chen G, et al. Progesterone administration modulates TLRs/NF-kappaB signaling pathway in rat brain after cortical contusion. Ann Clin Lab Sci. 2008;38(1):65–74.

    CAS  PubMed  Google Scholar 

  133. Hang CH, et al. Concomitant upregulation of nuclear factor-kB activity, proinflammatory cytokines and ICAM-1 in the injured brain after cortical contusion trauma in a rat model. Neurol India. 2005;53(3):312–7.

    Article  PubMed  Google Scholar 

  134. Yu ZQ, Zha JH. Genetic ablation of toll-like receptor 2 reduces secondary brain injury caused by cortical contusion in mice. Ann Clin Lab Sci. 2012;42(1):26–33.

    PubMed  Google Scholar 

  135. Ahmad A, et al. Absence of TLR4 reduces neurovascular unit and secondary inflammatory process after traumatic brain injury in mice. PLoS ONE. 2013;8(3): e57208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Fourgeaud L, et al. TAM receptors regulate multiple features of microglial physiology. Nature. 2016;532(7598):240–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kumar A, et al. Microglial/macrophage polarization dynamics following traumatic brain injury. J Neurotrauma. 2016;33(19):1732–50.

    Article  PubMed  PubMed Central  Google Scholar 

  138. Dohi K, et al. Gp91phox (NOX2) in classically activated microglia exacerbates traumatic brain injury. J Neuroinflamm. 2010;7:41.

    Article  Google Scholar 

  139. Henry RJ, et al. Microglial depletion with CSF1R inhibitor during chronic phase of experimental traumatic brain injury reduces neurodegeneration and neurological deficits. J Neurosci. 2020;40(14):2960–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Escartin C, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021;24(3):312–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Allen NJ, et al. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature. 2012;486(7403):410–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Tsai HH, et al. Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science. 2012;337(6092):358–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Chung WS, et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature. 2013;504(7480):394–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Molofsky AV, et al. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature. 2014;509(7499):189–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Alvarez JI, et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science. 2011;334(6063):1727–31.

    Article  CAS  PubMed  Google Scholar 

  146. Faulkner JR, et al. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci. 2004;24(9):2143–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Myer DJ, et al. Essential protective roles of reactive astrocytes in traumatic brain injury. Brain. 2006;129(Pt 10):2761–72.

    Article  CAS  PubMed  Google Scholar 

  148. Bush TG, et al. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron. 1999;23(2):297–308.

    Article  CAS  PubMed  Google Scholar 

  149. Villapol S, Byrnes KR, Symes AJ. Temporal dynamics of cerebral blood flow, cortical damage, apoptosis, astrocyte-vasculature interaction and astrogliosis in the pericontusional region after traumatic brain injury. Front Neurol. 2014;5:82.

    Article  PubMed  PubMed Central  Google Scholar 

  150. Glober NK, et al. Acetazolamide treatment prevents redistribution of astrocyte aquaporin 4 after murine traumatic brain injury. Neurosci J. 2019;2019:2831501.

    Article  PubMed  PubMed Central  Google Scholar 

  151. Jayakumar AR, et al. Activation of NF-kappaB mediates astrocyte swelling and brain edema in traumatic brain injury. J Neurotrauma. 2014;31(14):1249–57.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Gorse KM, et al. Transient receptor potential melastatin 4 induces astrocyte swelling but not death after diffuse traumatic brain injury. J Neurotrauma. 2018;35(14):1694–704.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Gupta RK, Prasad S. Early down regulation of the glial Kir4.1 and GLT-1 expression in pericontusional cortex of the old male mice subjected to traumatic brain injury. Biogerontology. 2013;14(5):531–41.

    Article  CAS  PubMed  Google Scholar 

  154. Gupta RK, Prasad S. Age-dependent alterations in the interactions of NF-kappaB and N-myc with GLT-1/EAAT2 promoter in the pericontusional cortex of mice subjected to traumatic brain injury. Mol Neurobiol. 2016;53(5):3377–88.

    Article  CAS  PubMed  Google Scholar 

  155. Rao VL, et al. Traumatic brain injury down-regulates glial glutamate transporter (GLT-1 and GLAST) proteins in rat brain. J Neurochem. 1998;70(5):2020–7.

    Article  CAS  PubMed  Google Scholar 

  156. Li YH, et al. Effects of mild induced hypothermia on hippocampal connexin 43 and glutamate transporter 1 expression following traumatic brain injury in rats. Mol Med Rep. 2015;11(3):1991–6.

    Article  CAS  PubMed  Google Scholar 

  157. Jiang H, et al. Toll-Like receptor 4 knockdown attenuates brain damage and neuroinflammation after traumatic brain injury via inhibiting neuronal autophagy and astrocyte activation. Cell Mol Neurobiol. 2018;38(5):1009–19.

    Article  CAS  PubMed  Google Scholar 

  158. Herx LM, Yong VW. Interleukin-1β is required for the early evolution of reactive astrogliosis following CNS lesion. J Neuropathol Exp Neurol. 2001;60(10):961–71.

    Article  CAS  PubMed  Google Scholar 

  159. Wang XY, et al. Endogenous TGFbeta1 plays a crucial role in functional recovery after traumatic brain injury associated with smad3 signal in rats. Neurochem Res. 2015;40(8):1671–80.

    Article  CAS  PubMed  Google Scholar 

  160. Toutonji A, et al. Chronic complement dysregulation drives neuroinflammation after traumatic brain injury: a transcriptomic study. Acta Neuropathol Commun. 2021;9(1):126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Arneson D, et al. Single cell molecular alterations reveal target cells and pathways of concussive brain injury. Nat Commun. 2018;9(1):3894.

    Article  PubMed  PubMed Central  Google Scholar 

  162. Todd BP, et al. Traumatic brain injury results in unique microglial and astrocyte transcriptomes enriched for type I interferon response. J Neuroinflamm. 2021;18(1):151.

    Article  CAS  Google Scholar 

  163. Arneson D, et al. Systems spatiotemporal dynamics of traumatic brain injury at single-cell resolution reveals humanin as a therapeutic target. Cell Mol Life Sci. 2022;79(9):480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Xing J, et al. Single-cell RNA sequencing reveals cellular and transcriptional changes associated with traumatic brain injury. Front Genet. 2022;13: 861428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Liddelow SA, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Clarke LE, et al. Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci USA. 2018;115(8):E1896–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Guttenplan KA, et al. Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature. 2021;599(7883):102–7.

    Article  CAS  PubMed  Google Scholar 

  168. Prescott K, et al. Blocking formation of neurotoxic reactive astrocytes is beneficial following stroke. biorxiv. 2023;33:330.

    Google Scholar 

  169. Morganti-Kossmann MC, et al. The complexity of neuroinflammation consequent to traumatic brain injury: from research evidence to potential treatments. Acta Neuropathol. 2019;137(5):731–55.

    Article  PubMed  Google Scholar 

  170. Simon DW, et al. The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol. 2017;13(9):572.

    Article  PubMed  Google Scholar 

  171. Weller RO, et al. The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS. Acta Neuropathol. 2018;135(3):363–85.

    Article  CAS  PubMed  Google Scholar 

  172. Nabeshima S, et al. Junctions in the meninges and marginal glia. J Comp Neurol. 1975;164(2):127–69.

    Article  CAS  PubMed  Google Scholar 

  173. Louveau A, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Absinta M, et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI. Elife. 2017. https://doi.org/10.7554/eLife.29738.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Aspelund A, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212(7):991–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Visanji NP, Lang AE, Munoz DG. Lymphatic vasculature in human dural superior sagittal sinus: Implications for neurodegenerative proteinopathies. Neurosci Lett. 2018;665:18–21.

    Article  CAS  PubMed  Google Scholar 

  177. Alcolado R, et al. The cranial arachnoid and pia mater in man: anatomical and ultrastructural observations. Neuropathol Appl Neurobiol. 1988;14(1):1–17.

    Article  CAS  PubMed  Google Scholar 

  178. Vandenabeele F, Creemers J, Lambrichts I. Ultrastructure of the human spinal arachnoid mater and dura mater. J Anat. 1996;189(Pt 2):417–30.

    PubMed  PubMed Central  Google Scholar 

  179. Balin BJ, et al. Avenues for entry of peripherally administered protein to the central nervous system in mouse, rat, and squirrel monkey. J Comp Neurol. 1986;251(2):260–80.

    Article  CAS  PubMed  Google Scholar 

  180. Vinas FC, et al. Microsurgical anatomy of the arachnoidal trabecular membranes and cisterns at the level of the tentorium. Neurol Res. 1996;18(4):305–12.

    Article  CAS  PubMed  Google Scholar 

  181. Dorrier CE, et al. Emerging roles for CNS fibroblasts in health, injury and disease. Nat Rev Neurosci. 2022;23(1):23–34.

    Article  CAS  PubMed  Google Scholar 

  182. Spector R, Robert Snodgrass S, Johanson CE. A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans. Exp Neurol. 2015;273:57–68.

    Article  CAS  PubMed  Google Scholar 

  183. Hannocks MJ, et al. Molecular characterization of perivascular drainage pathways in the murine brain. J Cereb Blood Flow Metab. 2018;38(4):669–86.

    Article  CAS  PubMed  Google Scholar 

  184. Pietila R, et al. Molecular anatomy of adult mouse leptomeninges. Neuron. 2023;111(23):3745–64.

    Article  PubMed  Google Scholar 

  185. Vanlandewijck M, et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018;554(7693):475–80.

    Article  CAS  PubMed  Google Scholar 

  186. Van Hove H, et al. A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat Neurosci. 2019;22(6):1021–35.

    Article  PubMed  Google Scholar 

  187. Brochner CB, Holst CB, Mollgard K. Outer brain barriers in rat and human development. Front Neurosci. 2015;9:75.

    Article  PubMed  PubMed Central  Google Scholar 

  188. Natale G, Bocci G, Ribatti D. Scholars and scientists in the history of the lymphatic system. J Anat. 2017;231(3):417–29.

    Article  PubMed  PubMed Central  Google Scholar 

  189. Mascagni P. Vasorum lymphaticorum corporis humani historia et ichnographia. (No Title), 1787.

  190. Sandrone S, et al. A (delayed) history of the brain lymphatic system. Nat Med. 2019;25(4):538–40.

    Article  CAS  PubMed  Google Scholar 

  191. Izen RM, et al. Postnatal development of lymphatic vasculature in the brain meninges. Dev Dyn. 2018;247(5):741–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Ahn JH, et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature. 2019;572(7767):62–6.

    Article  CAS  PubMed  Google Scholar 

  193. Jacob L, et al. Anatomy and function of the vertebral column lymphatic network in mice. Nat Commun. 2019;10(1):4594.

    Article  PubMed  PubMed Central  Google Scholar 

  194. Jacob L, et al. Conserved meningeal lymphatic drainage circuits in mice and humans. J Exp Med. 2022. https://doi.org/10.1084/jem.20220035.

    Article  PubMed  PubMed Central  Google Scholar 

  195. Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell. 1999;98(6):769–78.

    Article  CAS  PubMed  Google Scholar 

  196. Oliver G, Srinivasan RS. Endothelial cell plasticity: how to become and remain a lymphatic endothelial cell. Development. 2010;137(3):363–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Escobedo N, Oliver G. Lymphangiogenesis: origin, specification, and cell fate determination. Annu Rev Cell Dev Biol. 2016;32:677–91.

    Article  CAS  PubMed  Google Scholar 

  198. Francois M, et al. Sox18 induces development of the lymphatic vasculature in mice. Nature. 2008;456(7222):643–7.

    Article  CAS  PubMed  Google Scholar 

  199. Wigle JT, et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 2002;21(7):1505–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. You LR, et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature. 2005;435(7038):98–104.

    Article  CAS  PubMed  Google Scholar 

  201. Lin FJ, et al. Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development. J Clin Invest. 2010;120(5):1694–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Srinivasan RS, et al. The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev. 2010;24(7):696–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Oliver G. Lymphatic vasculature development. Nat Rev Immunol. 2004;4(1):35–45.

    Article  CAS  PubMed  Google Scholar 

  204. Tammela T, Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell. 2010;140(4):460–76.

    Article  CAS  PubMed  Google Scholar 

  205. Makinen T, et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med. 2001;7(2):199–205.

    Article  CAS  PubMed  Google Scholar 

  206. Karpanen T, et al. Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation. Am J Pathol. 2006;169(2):708–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Karkkainen MJ, et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004;5(1):74–80.

    Article  CAS  PubMed  Google Scholar 

  208. Yoshimatsu Y, Miyazaki H, Watabe T. Roles of signaling and transcriptional networks in pathological lymphangiogenesis. Adv Drug Deliv Rev. 2016;99(Pt B):161–71.

    Article  CAS  PubMed  Google Scholar 

  209. Karpanen T, Alitalo K. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol. 2008;3:367–97.

    Article  CAS  PubMed  Google Scholar 

  210. Antila S, et al. Development and plasticity of meningeal lymphatic vessels. J Exp Med. 2017;214(12):3645–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Rustenhoven J, et al. Functional characterization of the dural sinuses as a neuroimmune interface. Cell. 2021;184(4):1000–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Balint L, et al. Lymph flow induces the postnatal formation of mature and functional meningeal lymphatic vessels. Front Immunol. 2019;10:3043.

    Article  CAS  PubMed  Google Scholar 

  213. Oliver G, et al. The lymphatic vasculature in the 21(st) century: novel functional roles in homeostasis and disease. Cell. 2020;182(2):270–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Hammerling B, et al. The complexus adhaerens of mammalian lymphatic endothelia revisited: a junction even more complex than hitherto thought. Cell Tissue Res. 2006;324(1):55–67.

    Article  PubMed  Google Scholar 

  215. Yao LC, et al. Plasticity of button-like junctions in the endothelium of airway lymphatics in development and inflammation. Am J Pathol. 2012;180(6):2561–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Jannaway M, et al. VEGFR3 is required for button junction formation in lymphatic vessels. Cell Rep. 2023;42(7): 112777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Baluk P, et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med. 2007;204(10):2349–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Pflicke H, Sixt M. Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J Exp Med. 2009;206(13):2925–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Johnson LA, et al. Dendritic cells enter lymph vessels by hyaluronan-mediated docking to the endothelial receptor LYVE-1. Nat Immunol. 2017;18(7):762–70.

    Article  CAS  PubMed  Google Scholar 

  220. Baluk P, McDonald DM. Buttons and zippers: endothelial junctions in lymphatic vessels. Cold Spring Harb Perspect Med. 2022;12(12): a041178.

    Article  CAS  PubMed  Google Scholar 

  221. Weigel C, Bellaci J, Spiegel S. Sphingosine-1-phosphate and its receptors in vascular endothelial and lymphatic barrier function. J Biol Chem. 2023;299(6): 104775.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Petrova TV, Koh GY. Biological functions of lymphatic vessels. Science. 2020. https://doi.org/10.1126/science.aax4063.

    Article  PubMed  Google Scholar 

  223. Louveau A, et al. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest. 2017;127(9):3210–9.

    Article  PubMed  PubMed Central  Google Scholar 

  224. Kuo PH, et al. Meningeal lymphatic vessel flow runs countercurrent to venous flow in the superior sagittal sinus of the human brain. Tomography. 2018;4(3):99–104.

    Article  PubMed  PubMed Central  Google Scholar 

  225. Louveau A, et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature. Nat Neurosci. 2018;21(10):1380–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Albayram MS, et al. Non-invasive MR imaging of human brain lymphatic networks with connections to cervical lymph nodes. Nat Commun. 2022;13(1):203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Asano K, et al. Pre-collecting lymphatic vessels form detours following obstruction of lymphatic flow and function as collecting lymphatic vessels. PLoS ONE. 2020;15(1): e0227814.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Shah T, et al. Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma. J Exp Med. 2023. https://doi.org/10.1084/jem.20220618.

    Article  PubMed  Google Scholar 

  229. Smyth, L.C.D., et al., Identification of direct connections between the dura and the brain. Nature, 2024.

  230. Utz SG, et al. Early fate defines microglia and non-parenchymal brain macrophage development. Cell. 2020;181(3):557–73.

    Article  CAS  PubMed  Google Scholar 

  231. Alves de Lima K, et al. Meningeal γδ T cells regulate anxiety-like behavior via IL-17a signaling in neurons. Nat Immunol. 2020;21(11):1421–9.

    Article  CAS  PubMed  Google Scholar 

  232. Mazzitelli JA, et al. Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels. Nat Neurosci. 2022;25(5):555–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Cugurra A, et al. Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma. Science. 2021. https://doi.org/10.1126/science.abf7844.

    Article  PubMed  PubMed Central  Google Scholar 

  234. Brioschi S, et al. Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders. Science. 2021. https://doi.org/10.1126/science.abf9277.

    Article  PubMed  PubMed Central  Google Scholar 

  235. Herisson F, et al. Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat Neurosci. 2018;21(9):1209–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Mrdjen D, et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity. 2018;48(3):599.

    Article  CAS  PubMed  Google Scholar 

  237. Ajami B, et al. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat Neurosci. 2018;21(4):541–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Drieu A, et al. Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid. Nature. 2022;611(7936):585–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Da Mesquita S, et al. Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and beta-amyloid pathology. Sci Adv. 2021. https://doi.org/10.1126/sciadv.abe4601.

    Article  PubMed  PubMed Central  Google Scholar 

  240. Da Mesquita S, et al. Meningeal lymphatics affect microglia responses and anti-Abeta immunotherapy. Nature. 2021;593(7858):255–60.

    Article  PubMed  PubMed Central  Google Scholar 

  241. Gadani SP, et al. Characterization of meningeal type 2 innate lymphocytes and their response to CNS injury. J Exp Med. 2017;214(2):285–96.

    Article  CAS  PubMed  Google Scholar 

  242. Gate D, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature. 2020;577(7790):399–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Schafflick D, et al. Integrated single cell analysis of blood and cerebrospinal fluid leukocytes in multiple sclerosis. Nat Commun. 2020;11(1):247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Schlager C, et al. Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature. 2016;530(7590):349–53.

    Article  PubMed  Google Scholar 

  245. Merlini A, et al. Distinct roles of the meningeal layers in CNS autoimmunity. Nat Neurosci. 2022;25(7):887–99.

    Article  CAS  PubMed  Google Scholar 

  246. Lapenna A, De Palma M, Lewis CE. Perivascular macrophages in health and disease. Nat Rev Immunol. 2018;18(11):689–702.

    Article  CAS  PubMed  Google Scholar 

  247. Chakarov S, et al. Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science. 2019. https://doi.org/10.1126/science.aau0964.

    Article  PubMed  Google Scholar 

  248. Wang AZ, et al. Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response. Genome Med. 2022;14(1):49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Masuda T, et al. Specification of CNS macrophage subsets occurs postnatally in defined niches. Nature. 2022;604(7907):740–8.

    Article  CAS  PubMed  Google Scholar 

  250. Rojo R, et al. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations. Nat Commun. 2019;10(1):3215.

    Article  PubMed  PubMed Central  Google Scholar 

  251. Munro DAD, et al. CNS macrophages differentially rely on an intronic Csf1r enhancer for their development. Development. 2020. https://doi.org/10.1242/dev.194449.

    Article  PubMed  PubMed Central  Google Scholar 

  252. Rua R, et al. Infection drives meningeal engraftment by inflammatory monocytes that impairs CNS immunity. Nat Immunol. 2019;20(4):407–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Rebejac J, et al. Meningeal macrophages protect against viral neuroinfection. Immunity. 2022;55(11):2103–17.

    Article  CAS  PubMed  Google Scholar 

  254. Mundt S, et al. Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation. Sci Immunol. 2019. https://doi.org/10.1126/sciimmunol.aau8380.

    Article  PubMed  Google Scholar 

  255. Anandasabapathy N, et al. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J Exp Med. 2011;208(8):1695–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Ugur M, et al. Lymph node medulla regulates the spatiotemporal unfolding of resident dendritic cell networks. Immunity. 2023;56(8):1778-1793.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Clarkson BD, et al. CCR2-dependent dendritic cell accumulation in the central nervous system during early effector experimental autoimmune encephalomyelitis is essential for effector T cell restimulation in situ and disease progression. J Immunol. 2015;194(2):531–41.

    Article  CAS  PubMed  Google Scholar 

  258. Hatterer E, et al. How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes. Blood. 2006;107(2):806–12.

    Article  CAS  PubMed  Google Scholar 

  259. Hatterer E, et al. Cerebrospinal fluid dendritic cells infiltrate the brain parenchyma and target the cervical lymph nodes under neuroinflammatory conditions. PLoS ONE. 2008;3(10): e3321.

    Article  PubMed  PubMed Central  Google Scholar 

  260. Carson MJ, et al. Disproportionate recruitment of CD8+ T cells into the central nervous system by professional antigen-presenting cells. Am J Pathol. 1999;154(2):481–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Hu X, et al. Meningeal lymphatic vessels regulate brain tumor drainage and immunity. Cell Res. 2020;30(3):229–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Hsu M, et al. Neuroinflammation creates an immune regulatory niche at the meningeal lymphatic vasculature near the cribriform plate. Nat Immunol. 2022;23(4):581–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Goldmann J, et al. T cells traffic from brain to cervical lymph nodes via the cribroid plate and the nasal mucosa. J Leukoc Biol. 2006;80(4):797–801.

    Article  CAS  PubMed  Google Scholar 

  264. Bromley SK, Thomas SY, Luster AD. Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat Immunol. 2005;6(9):895–901.

    Article  CAS  PubMed  Google Scholar 

  265. Debes GF, et al. Chemokine receptor CCR7 required for T lymphocyte exit from peripheral tissues. Nat Immunol. 2005;6(9):889–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Kivisakk P, et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci USA. 2003;100(14):8389–94.

    Article  PubMed  PubMed Central  Google Scholar 

  267. de Graaf MT, et al. Central memory CD4+ T cells dominate the normal cerebrospinal fluid. Cytometry B Clin Cytom. 2011;80(1):43–50.

    Article  PubMed  Google Scholar 

  268. Filiano AJ, et al. Unexpected role of interferon-gamma in regulating neuronal connectivity and social behaviour. Nature. 2016;535(7612):425–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Derecki NC, et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med. 2010;207(5):1067–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Pasciuto E, et al. Microglia require CD4 T cells to complete the fetal-to-adult transition. Cell. 2020;182(3):625–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Ziv Y, et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci. 2006;9(2):268–75.

    Article  CAS  PubMed