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Table 1 Cytokines and chemokines involved in inflammation after SCI

From: Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration

Names

Aliases

Cells that secrete the cytokine/chemokine, receptors they bind to, and their effects after SCI

IL-1α

IL-1F1

Released via activated microglia and PDMs largely in response to disease, infection, or inflammatory events [52]

Binds to IL-1R1 [52]

Required for neutrophil recruitment during cell death-induced sterile inflammation [128]

IL-1β

IL-1F2

Produced by activated microglia and PDMs as a proprotein, which is proteolytically processed to its active form by caspase 1 (CASP1/ICE) [52, 129,130,131]

Binds to the IL-1R [129]

Plays a more substantial role than IL-1α post-SCI [52, 132, 133]

Stimulates inflammatory mediators including prostaglandins, cyclooxygenase 2, and phospholipase A2 [52, 129]

IL-2

Produced by activated T-cells [134]

Binds to IL-2R complex, which consists of IL-2Rα, IL-2Rβ, and the common γ-chain subunits [134]

Contributes to the proliferation of T-helpers [87]

Responsible for initiating the proper response of memory T-cells to invading pathogens [135]

IL-4

Produced by T-helper cells, eosinophils, basophils, and mast cells [136]

Binds to IL-4Rɑ, which will either dimerize with the common cytokine-receptor γ-chain and produce the type-1 signaling complex, or with IL-13Rα1 and produce the type-2 signaling complex [136, 53]

Increases microglia/macrophages expressing antigens characteristic of an anti-inflammatory M2 phenotype [70]

Increases the number of oligodendrocytes and neuronal markers βIII-tubulin and NeuN after SCI, suggesting a role in neuroprotection [137]

IL-5

Produced by hematopoietic and non-hematopoietic cells, including granulocytes, T-cells, and natural helper cells [138]

Binds to IL-5R and stimulates B-cell growth as well as increases immunoglobulin secretion (primarily IgA). Is also a key mediator in eosinophil activation [139, 140]

IL-6

Expressed in astrocytes, microglia and PDMs, and neurons [37]

Binds to IL-6R, which exists either as a membrane-bound receptor or a soluble receptor [141]

Activates inflammation and is a strong recruiter of immune cells after SCI [142]

Acts on neural stem cells to induce their differentiation into astrocytes [143]

IL-8

CXCL8

GRO (the rat analogue)

Produced by a wide variety of cells including monocytes, endothelial cells, T-cells, and macrophages [144]

Binds to CXCR1 and CXCR2 receptors [52]

Induces chemotaxis in neutrophils and granulocytes [52]

Upregulated for at least 14 days after SCI and strongly correlates with the extent of injury [87, 49, 38, 14]

IL-10

Produced by monocytes, B-cells, dendritic cells, natural killer cells, and T-cells [145]

Binds to IL-10R heterotetramer complex made of two IL-10R1 molecules and two IL-10R2 molecules [146]

Downregulates several pro-inflammatory cytokines and inflammatory species [56]

Provides trophic support to neurons through downregulation of pro-apoptotic factors and upregulation of anti-apoptotic factors [56]

IL-12

IL-12É‘

P35

Produced by dendritic cells, macrophages, monocytes, neutrophils, microglia cells, and B-cells [147]

Binds to IL-12R, which consists of the IL-12Rβ1 and IL-12Rβ2 chains [148]

IL-12(p70) expresses nitric oxide synthase and TNFα in microglia and PDMs [149]

IL-13

Produced by T-cells, dendritic cells, and activated Th2 cells [150]

Binds either to IL-13RÉ‘1 or IL-13RÉ‘2 [53, 151]

Involved in the production of transforming growth factor beta (TGF-β) [151]

IL-17É‘

IL-17

CTLA-8

Produced by several types of cells including T-cells, dendritic cells, and macrophages [152]

Binds to the A and C subunits of IL-17R [152]

IL-17 knockout mice showed increased locomotor function after SCI suggesting a role in regulating secondary degeneration of neural tissue [153]

TNF-É‘

TNF

TNFSF2

Produced by microglia, PDMs, astrocytes, oligodendrocytes, monocytes, and neurons [37, 39]

Two active forms are transmembrane TNFÉ‘ and soluble TNFÉ‘ [154]

Soluble TNFα is released by regulated cleavage of transmembrane TNFɑ by TNFɑ-converting enzyme (TACE/ADAM17) [154]

Binds to TNFR1 and TNFR2 [154]

Affects cell proliferation, differentiation, apoptosis, immunity, and inflammation [37]

Recruits macrophages to injury site [37]

IFN-γ

Produced by γẟ T-cells and leads to the activation of macrophages [95, 155]

Induces secretion of IL-10 from microglia and PDMs [155]

Can act synergistically with GM-CSF to promote the production of cytokines [156]

GM-CSF

CSF2

Produced by macrophages, mast cells, T-cells, fibroblasts, and endothelial cells in response to immune activation and cytokines that mediate inflammation [157]

Causes differentiation of hematopoietic progenitor cells into granulocytes, macrophages, and dendritic cells [158]

Can stimulate the proliferation of bone marrow stem cells and reduce leukocyte apoptosis, as well as cause microglia to proliferate and change their morphology [158]

GM-CSF-induced activation of microglia may promote functional recovery and axonal regeneration by release of brain-derived neurotrophic factor or by phagocytosis of myelin debris [159, 160]

MCP-1

CCL2

Secreted by activated T-cells, astrocytes, microglia, and monocytes [161]

Binds to CCR2 [106]

Activates and recruits mononuclear phagocytes, T-cells, and B-cells [162]

MIP-1É‘

CCL3

Secreted by activated T-cells, astrocytes, microglia, and monocytes [161]

Promotes chemotaxis of monocytes and T-cells [161]

Expression induced by pro-inflammatory stimulators, such as LPS, TNFα and IL-1β, and neuronal injury [163]

Can enhance the production of other pro-inflammatory cytokines via CCR1, CCR4, and CCR5 [163]

Impacts CNS inflammation through regulation of macrophages and astrocytes [163]

RANTES

CCL5

TCP228

Produced by astrocytes and is primarily involved in promoting migration of M2 macrophages [51]

Expression induced by IL-1 and macrophage migration inhibitory factor [51]

Binds to CCR1, CCR3, and CCR5 [164]

Associated with T-cell activation in SCI. Chronic T-cell activation subsequently contributes to neurodegeneration and inhibits repair of injured tissues [165]

Induces the migration and recruitment of a wide variety of cells including T-cells, dendritic cells, natural killer cells, eosinophils, basophils, mast cells, and endothelial progenitor cells [51]

May help amplify inflammatory response by facilitating the recruitment of inflammatory cells to the injury [51]

TGF-β1

Produced by lymphocytes, macrophages, and dendritic cells [166]

Binds to TGF-βR1, TGF-βR2, and TGF-βR3 [167]

Activates glial cells and phagocytes to form connective tissue and extracellular matrix [168]

Influences the differentiation, proliferation, and state of activation of leukocytes [166]

Known to suppress expression of MHC class II antigen [166]