Skip to main content

Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons

Abstract

An increasing number of studies show that the activation of the innate immune system and inflammatory mechanisms play an important role in the pathogenesis of numerous diseases. The innate immune system is present in almost all multicellular organisms and its activation occurs in response to pathogens or tissue injury via pattern-recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs). Intracellular pathways, linking immune and inflammatory response to ion channel expression and function, have been recently identified. Among ion channels, the transient receptor potential (TRP) channels are a major family of non-selective cation-permeable channels that function as polymodal cellular sensors involved in many physiological and pathological processes.

In this review, we summarize current knowledge of interactions between immune cells and PRRs and ion channels of TRP families with PAMPs and DAMPs to provide new insights into the pathogenesis of inflammatory diseases. TRP channels have been found to interfere with innate immunity via both nuclear factor-kB and procaspase-1 activation to generate the mature caspase-1 that cleaves pro-interleukin-1β cytokine into the mature interleukin-1β.

Sensory neurons are also adapted to recognize dangers by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli. As immune cells, they possess many of the same molecular recognition pathways for danger. Thus, they express PRRs including Toll-like receptors 3, 4, 7, and 9, and stimulation by Toll-like receptor ligands leads to induction of inward currents and sensitization in TRPs. In addition, the expression of inflammasomes in neurons and the involvement of TRPs in central nervous system diseases strongly support a role of TRPs in inflammasome-mediated neurodegenerative pathologies. This field is still at its beginning and further studies may be required.

Overall, these studies highlight the therapeutic potential of targeting the inflammasomes in proinflammatory, autoinflammatory and metabolic disorders associated with undesirable activation of the inflammasome by using specific TRP antagonists, anti-human TRP monoclonal antibody or different molecules able to abrogate the TRP channel-mediated inflammatory signals.

The inflammasome

The innate immune system plays an important role in the host’s first line of defense against microbial infections and involves the recognition of pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs) [1,2]. Activation of PRRs by microorganisms, toxins, chemical compounds, cytoplasmic PAMPs and/or endogenous DAMPS triggers intracellular signaling leading to inflammasome generation.

The PRR family of the innate immune system comprises: the membrane-bound Toll-like receptors (TLRs), C-type lectin receptors, retinoid acid-inducible gene-1-like receptors, and NOD-like receptors (NLRs; nucleotide-binding oligomerization domain receptors) [3].

The TLR family comprises type I transmembrane proteins with an extracellular binding domain composed of leucine-rich repeats and intracellular Toll-interleukin (IL)-1 receptor domains required for signals transduction [4,5]. Based on the TLR cellular localization and PAMP ligands, this family is divided into two groups. The first members (TLR3, TLR7, TLR8, and TLR9) are located in the endoplasmic reticulum (ER), endosomes and lysosomes; the second (TLR1, TLR2, TLR4, TLR5, and TLR6) are expressed on cell membranes and sense different PAMPs, including fungal cell wall components, lipopolysaccharide (LPS), bacterial flagella and peptidoglycan [6,7]. Upon activation, TLRs recruit a set of adaptor molecules such as MyD88 and Toll-IL-1-receptor domain-containing adaptor inducing interferon-β, and promote signaling events leading to the secretion of proinflammatory mediators [8].

The NLR family controls the inflammatory and immune responses via the activation of different signaling pathways involved in nuclear factor (NF)-κB activation (first signal) and caspase-1-mediated cleavage of IL-1β and IL-18 cytokines (second signals) [9]. NLR proteins share highly conserved structures and are divided into several subfamilies based on the nature of their N-terminal domains. NOD1 and NOD2 are two well-characterized members of non-inflammasome NLRs, which mediate NF-κB and mitogen-activated protein kinase activation in response to different PAMPs [10].

Inflammasomes are involved in defensive responses, dangerous inflammation and in pyroptosic cell death [11]. Structurally, the inflammasome is composed of the intracellular adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD) that recruits caspase-1 to the inflammasome complex and of a “sensor NLR” that functions as a molecular scaffold for the activation of caspase-1 for the final secretion of IL-1β and IL-18 [12]. Upon binding to the inflammasome, caspase-1 is cleaved and activated, leading to cleavage of different targets and causing maturation and secretion of the pro-inflammatory IL-1β. Several types of inflammasomes have been described containing different sensor proteins such as NLRP1, NLRP3, NLRP6, NLRP12, NLRP6, retinoid acid-inducible gene-1, AIM-2 and IPAF [9]. Among the NLR inflammasomes, the NLRP3 (nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3) is the most studied, and is activated by a broad range of signals of pathogenic, endogenous and environmental origin. NLRP3 is also activated by endogenous danger signal molecules released as a consequence of tissue injury, such as hyaluronan, extracellular ATP, uric acid crystals and amyloid-β fibrils, industrial particles and nanoparticles such as alum, asbestos, silica and titanium dioxide [9,13]. The mechanisms that have been suggested to mediate NLRP3 triggering are: potassium efflux, reactive oxygen species (ROS) production and alteration in the phagolysosomal [14,15] and lysosomal cathepsins activity [16]. In addition, the NLRP3 inflammasome regulates insulin signaling, the plaque formation in atherosclerosis, myocardial ischemia-reperfusion injury and neurodegeneration [17-19]. Recent data strongly support an important role played by the ion family of Transient Receptor Potential (TRP) channels that mediates interchanged and bidirectional contact and signaling with known PRRs, PAMPs and DAMPs in triggering the first and second signals responsible for inflammasome activation [20].

The TRP channel family

TRP channels are a family of non-selective cation channels that function as polymodal sensors in different physiological [21] and pathological processes [22]. The TRP channels are membrane proteins with six putative transmembrane segments (S1–S6) and a cation-permeable pore region between S5 and S6. About 30 different mammalian TRP channels are identified and classified into six subfamilies on the basis of sequence homology: TRP canonical (TRPC; TRPC1-7), TRP vanilloid (TRPV; TRPV1-6), TRP melastatin (TRPM; TRPM1-8), TRP polycystin (TRPP; TRPP2, TRPP3, TRPP5), TRP mucolipin (TRPML; TRPML1-3), and TRP ankyrin (TRPA; TRPA1) [23]. The different TRPs show distinct cation selectivity and gating mechanisms [24], and they can be opened by membrane depolarization, ligand binding, or G-protein coupled signaling [25].

TRPCs consist of proteins related to the “canonical” Drosophila TRP; functionally, the TRPC receptor family has been implicated in hypertension, cardiac hypertrophy, vascular inflammation, progressive kidney failure and cancer [26-29].

The TRPV channels are thermo- and chemo-sensitive channels composed of six members [30]. TRPV1 can be activated by a diverse range of stimuli, including membrane depolarization, noxious heat, vanilloid, endocannabinoids, extracellular protons and inflammatory mediators [31]. TRPV1 plays a pivotal role in pain and neurogenic inflammation [20]. Moreover, a role of this receptor in glioblastoma and bladder cancer has been reported [32,33]. TRPMs show high permeability to Ca2+ and Mg2+ [34,35].

Among TRPMs, TRPM1 functions as a tumor suppressor, and TRPM3 seems to be involved in etiology of amyotrophic lateral sclerosis [34]. TRPM2, TRPM4, and TRPM5 are reported to be sensitive to high temperatures. The best understood cold-sensitive TRP channel is TRPM8, which is activated when the temperature drops below about 20°C [35].

The TRPML subfamily consists of three members characterized by a large E1 loop, between S1 and S2, with several N-glycosylation sites.

The TRPP subfamily has three members, TRPP2, TRPP3, and TRPP5; mutations in TRPP2 lead to autosomal dominant polycystic kidney disease [36].

The TRPA1 channel is the only member of the TRPA subfamily; it is involved in pain and in chronic visceral inflammation [37].

A plethora of diseases are interconnected with alteration of the expression and function of TRP channels. This review focuses attention on the aspects of the interaction between TRP channels and PRRs and PAMPs/DAMPs in mediating inflammasome generation and triggering an inflammatory response.

The TRP receptors recognize environmental exogenous and endogenous danger signals released during trauma or tissue injury

Noxious stimuli and inflammatory recognition pathways trigger activation of different receptor types shared by cells of the immune and peripheral nervous systems. In particular, TRP channels recognize exogenous signals, DAMPs from the environment (for example, heat, acidity, chemicals) and endogenous danger signals released during trauma/tissue injury (for example, ATP, osmotic stress, uric acid, hydroxynonenals). Other types of cellular stress such as mechanical stress can be also sensed by TRP channels and can induce inflammation [38].

Local extracellular acidosis may promote inflammation at ischemic and inflammatory sites. Acidic extracellular pH triggers NLRP3 inflammasome activation and IL-1β secretion in human macrophages and represents a novel danger signal alerting the innate immunity [39]. The NLRP3 inflammasome complex triggers caspase-1-mediated maturation and secretion of IL-1β, one of the key proinflammatory cytokines. Rajamäki and colleagues have demonstrated that human macrophages exposed to pH 7.5 to 6.0 trigger a pH-dependent secretion of IL-1β and activation of caspase-1 through a mechanism involving the TRPV1 and K+ channels. Acidic extracellular pH causes rapid intracellular acidification and IL-1β-inducing effects. Moreover, the NLRP3 knockdown abolishes IL-1β secretion at acidic pH. Remarkably, alkaline extracellular pH inhibited IL-1β response to different NLRP3 activators. Overall these data suggest that acidic environment represents an endogenous danger signal alerting the innate immunity. Low pH contributes to the start of inflammation in acidosis-associated pathologies such as atherosclerosis, post-ischemic inflammatory responses and cancers [39]. Intracellular acidification evoked by extracellular acidosis is regulated through TRPV1 [40]; thus a role for this receptor in the transduction of acidic danger signals activating the inflammasome might be suggested.

TRPM8 receptor is differentially expressed in human immune cells and in primary sensory neurons [41,42]. Increased transcription of IL-1α, IL-1β, IL-6, and IL-8 cytokine genes in human lung epithelial cells through activation of a TRPM8 variant by exposure to cold temperatures has been reported [43]. Moreover, in a recent abstract presented at the ISSAID Congress 2013 by Stoffels and colleagues it has been hypothesized that in vivo cold exposure could result in a modulated inflammatory response through activation of temperature-sensitive ion channels [44]. Thus, exposure to cold, or ex vivo stimulation of peripheral blood mononuclear cells with menthol, a TRPM8 agonist, induces an exaggerated (local and systemic) cytokine inflammatory response, as evaluated at protein level by enzyme-linked immunosorbent assays in several human-derived cell lines, primary cells and skin biopsies. Activation of the temperature-sensitive TRPM8 channel via TLRs results in an enhanced IL-1β secretion and, likely, NLRP3 inflammasome formation [44].

Exposure to particulate crystals can induce oxidative stress in phagocytes, which triggers NLRP3 inflammasome-mediated IL-1β secretion, activating undesiderable inflammatory responses associated with both autoinflammatory and metabolic diseases. Although mitochondrial ROS have been found to play a central role in NLRP3 inflammasome activation, how the ROS signal causes NLRP3 assembly of the inflammasome is still unknown. Recently, it has been demonstrated that liposome activation of the NLRP3 inflammasome requires mitochondrial ROS. Stimulation of macrophages with liposomes/crystals induces ROS-dependent calcium influx via the TRPM2 channels, and macrophages deficient in TRPM2 display impaired NLRP3 inflammasome activation and IL-1β secretion [45,46]. In this regard, Trpm2 −/− mice were resistant to crystal-/liposome-induced IL-1β-mediated peritonitis in vivo. Moreover, TRPM2-deficient mice are also susceptible to Listeria monocytogenes infection [47], a known activator of NLRP3 inflammasome [48]. Therefore, targeting TRPM2 may be effective for treatment of NLRP3 inflammasome-associated inflammatory disorders. Recently, a close interaction between ER and mitochondria in response to NLRP3 inflammasome stimuli has been demonstrated [49]. Interestingly, Murakami and colleagues have showed that ER-derived calcium is essential for mitochondria to maintain a damaged state [50]. Mitochondrial damage induces release of mitochondrial DNA into the cytosol, which activates the inflammasome [51,52]. ROS released from damaged mitochondria activate the TRPM2 channel, which results in calcium influx across the plasma membrane. Thus, it appears that calcium mobilization represents a critical step during NLRP3 inflammasome activation. Calcium is a key signal for several cellular proteases, protein kinases and phospholipases involved in NLRP3 inflammasome activation. These calcium-dependent enzymes may proteolytically regulate the assembly of the NLRP3 inflammasome.

TRPA1 seems to be involved in the detection of reactive chemicals, including environmental irritants such as tear gas and industrial isothiocyanates; it is also activated during tissue injury by endogenous 4-hydroxynonenal and prostaglandins [53,54]. A role for this receptor in the inflammasome activation is in evaluation.

The role of TRPM7 and TRPV2 channels in osmotic stress and regulatory volume decrease responses in microglia

Changes in cell volume represent a specific signal in the regulation of important physiological processes [55,56]. Cells exhibit rapid volume-regulatory mechanisms to recover their functions in response to different signals. Alterations in osmosensing or osmosignaling are associated with ischemia, hyponatremia, hypothermia and intracellular acidosis [55,57]. Hypotonicity has been found to induce processing and release of IL-1β [58]. Low osmolarities stimulate macrophage swelling and a decrease in intracellular K+ and Cl levels, which activates a regulatory volume decrease (RVD) that is sensed by the NLRP3 inflammasome [59]. The RVD process is controlled by TRPM7 and TRPV2 channels expressed in macrophages. During RVD, TRPV2 is translocated to the plasma membrane where it induces permeabilization [60]. Hypotonicity induces lysosome destabilization and it is sensitive to a broad range of TRP channel blockers that suppress caspase-1 activation and IL-1β release. TRPV2 functions as an osmosensor, and TRPM7 as a controller of the RVD process [61-63]. Blocking TRPM7 function using high extracellular Mg2+ concentrations delays RVD, decreases cell permeabilization [64], and reduces IL-1β release in macrophages. In the THP-1 monocytic cell line, TRPV2 gene silencing decreases IL-1β release in response to hypotonicity, without affecting RVD [60]. A decrease in extracellular osmolarity induces phosphorylation and activation of TAK1 (transforming growth factor-β activated kinase-1) in the HeLa cell line [65]. Inhibition of TAK1 phosphorylation abrogates hypotonicity-induced caspase-1 activation and IL-1β processing and activation of TAK1 is abolished in the presence of BAPTA-AM, a selective Ca2+ and Mg2+ chelator, suggesting a pivotal role for TRP channels. Moreover the TRP channel inhibitor 2-APB is able to block TAK1 phosphorylation and, in TAK1-silenced cells, IL-1β release induced by hypotonicity is also reduced in macrophages [60].

It has been reported that membrane stretch and intracellular Ca2+ activate TAK1 [66,67]. After maximum stretch during cell swelling, endomembranes, derived from endosomes and lysosomes, are used to repair plasma membrane damage [68]. In macrophages, endomembrane fusion during RVD induces TRPV2 trafficking to the cell surface. TRP blockers are also effective in inhibiting monosodium urate (MSU) crystal- and nigericin-induced caspase-1 activation, but the specific involvement of TRP channels, particularly of TRPV2, in NLRP3 activation has still to be confirmed using genetic ablation in mouse models [69]. Overall, general blockers of TRP channels abolish the RVD (probably controlled by TRPM7), cell permeabilization (due to TRPV2) and caspase-1 activation.

TLR-mediated inflammatory response is associated with TRP channel-dependent Ca2+ signaling and inflammasome activation in immune cells

Intracellular Ca2+ represents a second messenger that participates in TLR4-dependent signaling; however, how intracellular Ca2+ is increased in response to microbial stimuli (for example, LPS) and how it affects the inflammatory response and inflammasome generation is still only partially understood.

Several studies have indicated that TLR-mediated immune responses are associated with TRP channel-dependent Ca2+ signaling. Tauseef and colleagues identified a function for TRPC6 in endothelial cells (ECs). They showed that TRPC6-dependent Ca2+ signaling was coupled with the TLR4 signaling pathway and hence contributing to LPS-induced EC permeability and NF-κB-dependent lung inflammation [70]. Deletion of TRPC6 renders mice resistant to this endotoxin-induced barrier dysfunction and inflammation, and protects against sepsis-induced lethality. In addition, they found that LPS induces diacylglycerol in ECs, which activates TRPC6 in a TLR4-dependent manner. TRPC6-mediated Ca2+ entry in turn activates myosin light chain kinase, a regulator of endothelial contractility [70]. Recently, in RAW264 macrophages, it has been shown that TRPV2-mediated intracellular Ca2+ mobilization is involved in LPS-induced expression of inflammatory cytokines (tumor necrosis factor-α and IL-6) in a NF-κB-dependent manner [71]. Thus, it is tempting to speculate a role for TRPV2 in modulating TLR4-dependent signaling. Among TRPMs, TRPM4 is involved in LPS-induced EC death, and inhibition of TRPM4 activity protects the endothelium against LPS injury [72].

Higher levels of inflammasome components have been detected in the gingival tissues from patients with chronic periodontitis. Data obtained in differentiated THP-1 cells infected with Porphyromonas gingivalis, the major pathogen involved in the pathogenesis of periodontitis [73], evidenced that the microorganism induces IL-1β secretion, caspase-1 activation and pyroptotic cell death through both NLRP3 and AIM2 inflammasome activation [74]. The activation of the NLRP3 inflammasome is mediated by ATP release, P2X7 receptor and lysosomal damage. In addition, the priming signal is triggered via TLR2 and TLR4 activation precede P. gingivalis-induced IL-1β release [74]. Moreover, the expression of TRPV1 and TLR4 found in keratinocytes, fibroblasts, inflammatory cells and capillary endothelial cells in patients with aggressive and chronic periodontitis [75] suggests a role for TRPV1 signaling in the induction of the NLRP3 inflammasome.

Membrane TLRs respond to specific microbial components, including proteins of the virus envelopes, inducing cytokine release. The envelope protein hemagglutinins of MV (Measles Virus) and fusion protein of RSV (Respiratory Syncytial Virus) are known to interact with TLR2 and TLR4, and this effect upregulates TRP channels [76]. In particular RSV, MV and RV (Rhinovirus) induce TRPV1 and TRPA1 upregulation in bronchial epithelium, airway nerves and smooth muscle cells, with higher levels in asthmatic patients. Early upregulation of TRPA1 and TRPV1 expression in differentiated IMR-32 neuroblastoma cells is evidenced at 2 to 4 hours post-RV HRV-16 infection. This effect is independent of replicating virus, as virus-induced soluble factor alone is sufficient to increase TRP channel expression and augment nerve growth factor (NGF), IL-6, IL-8 and IL-1β levels in the supernatant of infected cells. By contrast, TRPM8 expression is maximal at 48 hours, and requires virus replication rather than soluble factors [76].

Further studies are required to completely understand the relationship between TLRs and TRP channels, cytokines, inflammasome activation and inflammatory response generation. The understanding of these interactions is crucial, as they may represent a novel potential therapeutic target and strategy for the treatment of chronic or acute inflammatory diseases by using TRPV1 and/or TRPA1 antagonists.

Danger recognition pathways in the peripheral nervous system and potential role of TRP channels in the inflammasome responses

During tissue damage and pathogenic infections, release of danger signals lead to a coordinated activation of an integrated host defense formed by both peripheral neurons and immune cells which activates a complex bidirectional communication through synthesis or release of neuropeptides, neurotransmitters, hormones and cytokines. Peripheral sensory neurons are adapted to recognize danger by virtue of their sensitivity to intense mechanical, thermal and irritant chemical stimuli. In this regard, TRP ion channels are the most widely studied molecular mediators of nociception, conducting non-selective entry of cations upon activation by various noxious stimuli [77]. The anatomic position of sensory neurons at the interface with the environment, their ability to release a set of immune-acting mediators and the velocity of neural signal transduction allows the peripheral nervous system to immuno-modulate the innate and adaptive responses. By contrast, sensory neurons are very sensitive to immune mediators, which trigger and sensitize neurons [77]. Thus, neurogenic and immune-mediated types of inflammation act together as early warning devices. Nociceptor neurons in the peripheral nervous system possess many of the same molecular recognition pathways for danger as immune cells, and the line between PRRs and noxious ligand-gated ion channels is increasingly blurred.

Peripheral and terminal axons have been found to induce a rapid and local release of neural mediators during the neurogenic inflammation, independently of that produced by the immune cell system. Neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P, adrenomedullin, neurokinins A and B, vasoactive intestinal peptide, neuropeptide Y, and gastrin-releasing peptide, as well as glutamate, nitric oxide, and cytokines and chemokines [78] from nociceptors, directly attract and activate innate and adaptive immune cells [79-81]. In this regard, it has been hypothesized that substance P is able to activate the NALP1 inflammasome. Furthermore, LY303870, a NK1 receptor antagonist, blocked the upregulation of activated NALP1 inflammasome components and IL-1β and IL-18 generation in a rat fracture model of complex regional pain syndrome [82].

Another key component of the immune/sensory neuron communication system are cytokines. In early phases of inflammation, sensory neurons signal to tissue resident mast cells and dendritic cells to induce degranulation or cytokine production [79,83]. IL-1β and tumor necrosis factor-α released by innate immune cells are directly sensed during inflammation by nociceptors which express the cognate receptors [84-86]. Upon activation of cytokine receptors, signal pathways are activated in nociceptors, inducing activation of membrane proteins including TRP channels [77]. The consequent sensitization of sensory neurons means that innocuous mechanical and heat stimuli can trigger nociceptors. Interestingly, sensory neurons share many of the same pathogen and danger molecular recognition receptor pathways as innate immune cells, which enable them also to recognize pathogens [77]. As in the immune system, sensory neurons express PRRs including TLR3/4/7/9, and stimulation by their ligands induces inward currents and nociceptor sensitization [87-89]. Activation of sensory neurons by the TLR7 ligand imiquimod leads to activation of an itch-specific sensory pathway [87]. A functional expression of the IL-31RA receptor, showing a critical role in the neuroimmune link between T helper 2 cells and sensory neurons for the generation of T-cell mediated itch, was evidenced in a small subpopulation of IL-31RA(+)/TRPV1(+)/TRPA1(+) neurons [90]. In addition extracellular microRNAs (let-7b miRNA) via the TLR7 receptor that couples TRPA1 activates nociceptor neurons to elicit pain [91]. TLR4 also enhances histamine-mediated pruritus by potentiating TRPV1 activity in dorsal root ganglion (DRG) sensory neurons [92]. Furthermore, in trigeminal neurons, LPS sensitizes TRPV1 to capsaicin, which is blocked by a selective TLR4 antagonist [88]; LPS or P. gingivalis infection has been demonstrated to increase capsaicin-evoked release of CGRP and TRPV1 sensitization in capsaicin-sensitive nociceptors [93] and down-regulates NLRP3 inflammasome expression [94]. Respiratory virus infections can upregulate TRPV1 and TRPA1 in airway nerves with higher expression levels in asthmatic patients [76]. Overall, these data suggest the expression of a TRPV1/CGRP/TLR4 axis mediating a cross-talk between neural and immune receptors during innate immune responses through the peripheral release of neuronal signaling molecules, and the induction of infection-associated pain and itch may be partly due to direct activation of neurons by pathogen-derived factors. In addition, endotoxin by inducing TLR4 activation of TRPC6-dependent calcium signaling induces vascular permeability and inflammation in the lung [70].

Amongst the DAMP/alarmin, extracellular ATP represents the major signals recognized by sensory neurons. It is a potent danger signal that activates both peripheral neurons during cellular injury, and some evidence even suggests that neurons express components of the inflammasome molecular machinery [95]. The ATP is recognized by purinergic and TRP receptors on both nociceptor neurons [96,97]. Purinergic receptors are made up of two families: P2X receptors (ligand-gated cation channels) and P2Y receptors (G-protein coupled receptors). In nociceptor neurons, recognition of ATP through P2Y receptors contributes to nociceptor activation by TRP sensitization. Thus, in sensory neurons, the triggering of P2Y2 receptor by ATP activates the TRPV1 channel in the absence of any other stimuli [98]. In macrophages, ATP binding to P2X7 receptors induces hyperpolarization and downstream activation of the inflammasome [99].

In addition, MSU or H2O2 injection into the hind paws of rodents or application to sensory neurons increased the expression of TRPA1 and TRPV1, and enhanced cellular infiltration and IL-1β levels; these effects were blocked by TRPA1 antagonists [100]. Moreover, MSU-induced pain-like behavior, hyperalgesia, allodynia, articular edema as well as plasma extravasation, leukocyte infiltration and IL-1β production were inhibited by co-administration of a selective TRPV1 antagonist, SB366791 [101]. Mechanical hypersensitivity evoked by intraplantar injection of LPS was prevented by the TRPA1 antagonist (AP-18) and was absent in Trpa1(−/−) mice, indicating that H2S-mediated stimulation of TRPA1 is necessary for local pro-nociceptive effects of LPS [102].

Inflammasome-forming NLRs in neurons of central nervous system and TRP channel involvement in neurodegenerative diseases

Inflammation in the central nervous system (CNS) has both pathogenic and protective effects depending on the clinical context. Increasing evidence suggests that inflammasomes exist in CNS cells such as neurons, astrocytes and microglia. Inflammasomes function as intracellular sensors for infectious agents as well as for host-derived danger signals and several studies have reported caspase-1 activation, IL-1β cleavage and expression of inflammasome-forming NLRs in neurons [60,103-106], as well as NLRP2 inflammasome expression in astrocytes [107]. The activation of the inflammasomes in the CNS are involved in the generation of an innate immune inflammatory response through IL-1β and IL-18 cytokine release and in cell death through the process of pyroptosis [108]. In the CNS, microglia, astrocytes and neurons express receptors for these cytokines, which thereby participate in systemic responses such as fever as well as in local inflammation within neural tissue [109,110].

Inflammasome activation is under current investigation across a broad spectrum of neurological diseases including infections, acute sterile brain injury and chronic neurodegenerative diseases. For a timely and extensive discussion on inflammasomes in CNS degenerative diseases, we direct the reader to a recent review by Walsh and colleagues, published in 2014 in Nature Review Neuroscience [108].

Perturbations of neuronal Ca2+ homeostasis are involved in the pathogenesis of several neurodegenerative disorders [111,112]. Thus, in amyotrophic lateral sclerosis/Parkinson dementia, high oxidative stress induces TRPM2 as well as TRPM7 activation leading to neurodegeneration [113]; in Parkinson's disease, dopaminergic neurons, along with coupling of mGluR1 with TRPC1/3/5 channels, results in alteration of neuronal activity [114,115]. TRPV1 and TRPV2 agonists diminished dopamine depletion and tyrosine hydroxylase deficits caused by the neurotoxin 6-hydroxydopamine in the striatum [116] and overexpression of TRPC1 increased dopaminergic neuron survival following MPP neurotoxin administration [117]. TRPM7-associated Mg2+-inhibited cation channel activity plays a role in neurodegenerative variations associated with Alzheimer's disease (AD) [118]; in AD, presenilin-2 negatively influences the TRPC6-dependent calcium entry [119] and inhibition of TRPM2 by siRNA reduces amyloid-β toxicity, suggesting a role for TRPM2 in neuronal cell death [120]. By contrast, in AD activation of TRPM7 leads to zinc accumulation and zinc-induced neurotoxicity [121]. TRPM2 and TRPM7 contribute to ischemic neural death and dysfunction, and their inhibition or gene silencing increased neuronal survival during ischemia [122].

Inflammasome proteins and even the functional machinery of inflammasomes have been linked to cell death in several cell types [123]. Tissue damage caused by oxidative stress has been found to play a pathogenetic role in several chronic neurodegenerative diseases such as AD and Parkinson’s disease. Substantial evidence supports the conclusion that TRP channels, in particular the TRPM2 channel, link cell death induced by oxidative stress [120] with the NLRP3 inflammasome activation [124].

Amyloid-β, the chief constituent of senile plaques in Alzheimer’s disease, was the first molecule associated with a neurodegenerative disease to be shown to activate the inflammasome (for example, NLRP3) [125,126]. Amyloid β-peptide and H2O2 have been found to induce cell death in primary cultures of rat striatal cells which express TRPM2 [120]. Four physiological splice variants of TRPM2 have been identified at present: TRPM2-L (full length or wild-type), TRPM2-S, TRPM2-ΔN and TRPM2-ΔC [127]. In striatal cells, the dominant negative splice variant TRPM2-S inhibits both amyloid β-peptide and H2O2-induced increase in [Ca2+]i and protects cell viability. Moreover, reduction in endogenous TRPM2 levels by RNA interference significantly enhances cell viability after β-peptide and H2O2 treatment.

Overall, these data provide significant support to the conclusion that TRPM2 is involved in oxidative stress-induced injury to striatal cells and, through activation by amyloid β-peptide, may be involved in the pathogenesis of AD [127].

Further studies may be required to completely assess the involvement of TRP channel signaling in inflammasome activation in neurodegenerative diseases.

Conclusions

Overall, the findings recently reported strongly suggest an important role played by ion channels belonging to the TRP channel families that mediates interchanged and bidirectional contact and intracellular signals with known PAMPs and DAMPs in inflammasome activation in immune and sensory nervous cells (Table 1). The development of new drugs to target inflammasome functions are now promising possibilities for future therapeutic interventions in neurological diseases. These results highlight the therapeutic potential of targeting different TRP channels by using TRP antagonists, or different molecules able to inhibit the TRP-induced signaling pathway, in autoinflammatory and metabolic disorders associated with undesirable activation and generation of the inflammasome.

Table 1 DAMP/PAMP recognition by TRP channels and PRRs triggers the inflammasome activation in immune and neuron cells

Abbreviations

AD:

Alzheimer's disease

CGRP:

calcitonin gene-related peptide

CNS:

central nervous system

DAMP:

danger-associated molecular pattern

EC:

endothelial cell

ER:

endoplasmic reticulum

IL:

interleukin

LPS:

lipopolysaccharide

MSU:

monosodium urate

NF:

nuclear factor

NLR:

NOD-like receptor (nucleotide-binding oligomerization domain receptor)

PAMP:

pathogen-associated molecular pattern

PRR:

pattern recognition receptor

ROS:

reactive oxygen species

RVD:

regulatory volume decrease

TLR:

Toll-like receptor

TRP:

transient receptor potential

References

  1. Fukata M, Vamadevan AS, Abreu MT. Toll-like receptors(TLRs) and Nod-like receptors (NLRs) in inflammatory disorders. Semin Immunol. 2009;21:242–53.

    CAS  PubMed  Google Scholar 

  2. Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. 2012;28:137–61.

    CAS  PubMed  Google Scholar 

  3. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–20.

    CAS  PubMed  Google Scholar 

  4. Carneiro LA, Magalhaes JG, Tattoli I, Philpott DJ, Travassos LH. Nod-like proteins in inflammation and disease. J Pathol. 2008;214:136–48.

    CAS  PubMed  Google Scholar 

  5. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–84.

    CAS  PubMed  Google Scholar 

  6. Brown J, Wang H, Hajishengallis GN, Martin M. TLR-signaling networks: an integration of adaptor molecules, kinases, and cross-talk. J Dent Res. 2011;90:417–27.

    PubMed Central  CAS  PubMed  Google Scholar 

  7. Jacobs SR, Damania B. NLRs, inflammasomes, and viral infection. J Leukoc Biol. 2012;92:469–77.

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity. 2010;32:305–15.

    CAS  PubMed  Google Scholar 

  9. Schorder K, Tschopp J. The inflammasomes. Cell. 2010;140:821–32.

    Google Scholar 

  10. Inohara C, McDonald C, Nuñez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem. 2005;74:355–83.

    CAS  PubMed  Google Scholar 

  11. Strowig T, Henao-Mejia J, Elinav E, Flavell R. Inflammasomes in health and disease. Nature. 2012;481:278–86.

    CAS  PubMed  Google Scholar 

  12. Wilson SP, Cassel SL. Inflammasome-mediated autoinflammatory disorders. Postgrad Med. 2010;122:125–33.

    PubMed Central  PubMed  Google Scholar 

  13. Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, et al. The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A. 2008;105:9035–40.

    PubMed Central  CAS  PubMed  Google Scholar 

  14. Pétrilli V, Dostert C, Muruve DA, Tschopp J. The inflammasome: a danger sensing complex triggering innate immunity. Curr Opin Immunol. 2007;19:615–22.

    PubMed  Google Scholar 

  15. Sorbara MT, Girardin SE. Mitochondrial ROS fuel the inflammasome. Cell Res. 2011;21:558–60.

    PubMed Central  PubMed  Google Scholar 

  16. Gross O, Thomas CJ, Guarda G, Tschopp J. The inflammasome: an integrated view. Immunol Rev. 2011;243:136–51.

    CAS  PubMed  Google Scholar 

  17. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigated obesity-induced inflammation and insulin resistance. Nat Med. 2011;17:179–88.

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Grundmann S, Bode C, Moser M. Inflammasome activation in reperfusion injury: friendly fire on myocardial infarction? Circulation. 2011;123:574–6.

    PubMed  Google Scholar 

  19. Mathew A, Lindsley TA, Sheridan A, Bhoiwala DL, Hushmendy SF, Yager EJ, et al. Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration. J Alzheimers Dis. 2012;30:617–27.

    CAS  PubMed  Google Scholar 

  20. White JP, Urban L, Nagy I. TRPV1 function in health and disease. Curr Pharm Biotechnol. 2011;12:130–44.

    CAS  PubMed  Google Scholar 

  21. Nilius B, Owsianik G. The transient receptor potential family of ion channels. Genome Biol. 2011;12:218.

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Santoni G, Farfariello V, Amantini C. TRPV channels in tumor growth and progression. Adv Exp Med Biol. 2011;704:947–67.

    CAS  PubMed  Google Scholar 

  23. Nilius B, Owsianik G. Transient receptor potential channelopathies. Pflugers Arch. 2010;460:437–50.

    CAS  PubMed  Google Scholar 

  24. Vennekens R. Emerging concepts for the role of TRP channels in the cardiovascular system. J Physiol. 2011;589:1527–34.

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Kim H, Kim J, Jeon J, Myeong J, Wie J, Hong C, et al. The roles of G proteins in the activation of TRPC4 and TRPC5 transient receptor potential channels. Channels (Austin). 2012;6:333–43.

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005;37:739–44.

    PubMed Central  CAS  PubMed  Google Scholar 

  27. Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y, et al. TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. EMBO J. 2006;25:5305–16.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Wang P, Liu D, Tepel M, Zhu Z. Transient receptor potential canonical type 3 channels - their evolving role in hypertension and its related complications. J Cardiovasc Pharmacol. 2013;61:455–60.

    CAS  PubMed  Google Scholar 

  29. Wang D, Li X, Liu J, Li J, Li LJ, Qiu MX. Effects of TRPC6 on invasibility of low-differentiated prostate cancer cells. Asian Pac J Trop Med. 2014;7:44–7.

    CAS  PubMed  Google Scholar 

  30. Woudenberg-Vrenken TE, Bindels RJ, Hoenderop JG. The role of transient receptor potential channels in kidney disease. Nat Rev Nephrol. 2009;5:441–9.

    CAS  PubMed  Google Scholar 

  31. Holzer P, Izzo AA. The pharmacology of TRP channels. Br J Pharmacol. 2014;171:2469–73.

    CAS  PubMed  Google Scholar 

  32. Amantini C, Mosca M, Nabissi M, Lucciarini R, Caprodossi S, Arcella A, et al. Capsaicin-induced apoptosis of glioma cells is mediated by TRPV1 vanilloid receptor and requires p38 MAPK activation. J Neurochem. 2007;102:977–90.

    CAS  PubMed  Google Scholar 

  33. Caprodossi S, Amantini C, Nabissi M, Morelli MB, Farfariello V, Santoni M, et al. Capsaicin promotes a more aggressive gene expression phenotype and invasiveness in null-TRPV1 urothelial cancer cells. Carcinogenesis. 2011;32:686–94.

    CAS  PubMed  Google Scholar 

  34. Chubanov V, Waldegger S. Mederos y Schnitzler M, Vitzthum H, Sassen MC, Seyberth HW, Konrad M, Gudermann T. Disruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia. Proc Natl Acad Sci U S A. 2004;101:2894–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Zheng J. Molecular mechanism of TRP Channels. Compr Physiol. 2013;3:221–42.

    PubMed Central  PubMed  Google Scholar 

  36. Tsiokas L. Function and regulation of TRPP2 at the plasma membrane. Am J Physiol Renal Physiol. 2009;297:F1–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  37. Lapointe TK, Altier C. The role of TRPA1 in visceral inflammation and pain. Channels (Austin). 2011;5:525–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Clapham DE. TRP channels as cellular sensors. Nature. 2003;426:517–24.

    CAS  PubMed  Google Scholar 

  39. Rajamäki K, Nordström T, Nurmi K, Åkerman KE, Kovanen PT, Öörni K, et al. Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome. J Biol Chem. 2013;288:13410–9.

    PubMed Central  PubMed  Google Scholar 

  40. Chung S, Kim YH, Koh JY, Nam TS, Ahn DS. Intracellular acidification evoked by moderate extracellular acidosis attenuates transient receptor potential V1 (TRPV1) channel activity in rat dorsal root ganglion neurons. Exp Physiol. 2011;96:1270–81.

    CAS  PubMed  Google Scholar 

  41. Madrid R, Donovan-Rodríguez T, Meseguer V, Acosta MC, Belmonte C, Viana F. Contribution of TRPM8 channels to cold transduction in primary sensory neurons and peripheral nerve terminals. J Neurosci. 2006;26:12512–25.

    CAS  PubMed  Google Scholar 

  42. Wu SN, Wu PY, Tsai ML. Characterization of TRPM8-like channels activated by the cooling agent icilin in the macrophage cell line RAW 264.7. J Membr Biol. 2011;241:11–20.

    CAS  PubMed  Google Scholar 

  43. Sabnis AS, Reilly CA, Veranth JM, Yost GS. Increased transcription of cytokine genes in human lung epithelial cells through activation of a TRPM8 variant by cold temperature. Am J Physiol Lung Cell Mol Physiol. 2008;295:194–200.

    Google Scholar 

  44. Stoffels M, Remijn T, Elders LM, de Koning HD, van der Meer JW, Simon A. A role for thermo-TRP channels in innate immunity? [abstract]. Pediatric Rheumatol. 2013;11 Suppl 1:A176.

    Google Scholar 

  45. Yamamoto S, Shimizu S, Kiyonaka S, Takahashi N, Wajima T, Hara Y, et al. TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nat Med. 2008;14:738–47.

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Hecquet CM, Malik AB. Role of H(2)O(2)-activated TRPM2 calcium channel in oxidant-induced endothelial injury. Thromb Haemost. 2009;101:619–25.

    PubMed Central  CAS  PubMed  Google Scholar 

  47. Knowles H, Heizer JW, Li Y, Chapman K, Ogden CA, Andreasen K, et al. Transient Receptor Potential Melastatin 2 (TRPM2) ion channels is required for innate immunity against Listeria monocytogenes. Proc Natl Acad Sci U S A. 2011;108:11578–83.

    PubMed Central  CAS  PubMed  Google Scholar 

  48. Kim S, Bauernfeind F, Ablasser A, Hartmann G, Fitzgerald KA, Latz E, et al. Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome. Eur J Immunol. 2010;40:1545–51.

    PubMed Central  CAS  PubMed  Google Scholar 

  49. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469:221–5.

    CAS  PubMed  Google Scholar 

  50. Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM, et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A. 2012;109:11282–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  51. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12:222–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  52. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401–14.

    PubMed Central  CAS  PubMed  Google Scholar 

  53. Cruz-Orengo L, Dhaka A, Heuermann RJ, Young TJ, Montana MC, Cavanaugh EJ, et al. Cutaneous nociception evoked by 15-delta PGJ2 via activation of ion channel TRPA1. Mol Pain. 2008;4:30.

    PubMed Central  PubMed  Google Scholar 

  54. Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, et al. 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A. 2007;104:13519–24.

    PubMed Central  CAS  PubMed  Google Scholar 

  55. Hoffmann EK, Lambert IH, Pedersen SF. Physiology of cell volume regulation in vertebrates. Physiol Rev. 2009;89:193–277.

    CAS  PubMed  Google Scholar 

  56. Lang F, Lepple-Wienhues A, Szabó I, Siemen D, Gulbins E. Cell volume in cell proliferation and apoptotic cell death. Contrib Nephrol. 1998;123:158–68.

    CAS  PubMed  Google Scholar 

  57. Newman PJ, Grana WA. The changes in human synovial fluid osmolality associated with traumatic or mechanical abnormalities of the knee. Arthroscopy. 1988;4:179–81.

    CAS  PubMed  Google Scholar 

  58. Perregaux DG, Laliberte RE, Gabel CA. Human monocyte interleukin-1beta posttranslational processing. Evidence of a volume-regulated response. J Biol Chem. 1996;271:29830–8.

    CAS  PubMed  Google Scholar 

  59. Schorn C, Frey B, Lauber K, Janko C, Strysio M, Keppeler H, et al. Sodium overload and water influx activate the NALP3 inflammasome. J Biol Chem. 2011;286:35–41.

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Compan V, Baroja-Mazo A, Lopez-Castejon G, Gomez AI, Bazan E, Reimers D, et al. Cell volume regulation modulates NLRP3 inflammasome activation. Immunity. 2012;37:487–500.

    CAS  PubMed  Google Scholar 

  61. Liedtke W. Transient receptor potential vanilloid channels functioning in transduction of osmotic stimuli. J Endocrinol. 2006;191:515–23.

    CAS  PubMed  Google Scholar 

  62. Muraki K, Iwata Y, Katanosaka Y, Ito T, Ohya S, Shigekawa M, et al. TRPV2 is a component of osmotically sensitive cation channels in murine aortic myocytes. Circ Res. 2003;93:829–38.

    CAS  PubMed  Google Scholar 

  63. Numata T, Shimizu T, Okada Y. TRPM7 is a stretch- and swelling-activated cation channel involved in volume regulation in human epithelial cells. Am J Physiol Cell Physiol. 2007;292:C460–7.

    CAS  PubMed  Google Scholar 

  64. Penner R, Fleig A. The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7. Handb Exp Pharmacol. 2007;179:313–28.

    CAS  PubMed  Google Scholar 

  65. Sakurai H, Miyoshi H, Mizukami J, Sugita T. Phosphorylation-dependent activation of TAK1 mitogen-activated protein kinase kinase kinase by TAB1. FEBS Lett. 2000;474:141–5.

    CAS  PubMed  Google Scholar 

  66. Fukuno N, Matsui H, Kanda Y, Suzuki O, Matsumoto K, Sasaki K, et al. TGF-β-activated kinase 1 mediates mechanical stress-induced IL-6 expression in osteoblasts. Biochem Biophys Res Commun. 2011;408:202–7.

    CAS  PubMed  Google Scholar 

  67. Gong YN, Wang X, Wang J, Yang Z, Li S, Yang J, et al. Chemical probing reveals insights into the signaling mechanism of inflammasome activation. Cell Res. 2010;20:1289–305.

    CAS  PubMed  Google Scholar 

  68. Togo T, Alderton JM, Steinhardt RA. The mechanism of cell membrane repair. Zygote. 2000;8:S31–2.

    PubMed  Google Scholar 

  69. Link TM, Park U, Vonakis BM, Raben DM, Soloski MJ, Caterina MJ. TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nat Immunol. 2010;11:232–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Tauseef M, Knezevic N, Chava KR, Smith M, Sukriti S, Gianaris N, et al. TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation. J Exp Med. 2012;209:1953–68.

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Yamashiro K, Sasano T, Tojo K, Namekata I, Kurokawa J, Sawada N, et al. Role of transient receptor potential vanilloid 2 in LPS-induced cytokine production in macrophages. Biochem Biophys Res Commun. 2010;398:284–9.

    CAS  PubMed  Google Scholar 

  72. Becerra A, Echeverría C, Varela D, Sarmiento D, Armisén R, Nuñez-Villena F, et al. Transient receptor potential melastatin 4 inhibition prevents lipopolysaccharide-induced endothelial cell death. Cardiovasc Res. 2011;91:677–84.

    CAS  PubMed  Google Scholar 

  73. Darveau RP. Porphyromonas gingivalis neutrophil manipulation: risk factor for periodontitis?. Trends Microbiol. in press.

  74. Taxman DJ, Swanson KV, Broglie PM, Wen H, Holley-Guthrie E, Huang MT, et al. Porphyromonas gingivalis mediates inflammasome repression in polymicrobial cultures through a novel mechanism involving reduced endocytosis. J Biol Chem. 2012;287:32791–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  75. Ozturk A, Yildiz L. Expression of transient receptor potential vanilloid receptor 1 and toll-like receptor 4 in aggressive periodontitis and in chronic periodontitis. J Periodontal Res. 2011;46:475–82.

    CAS  PubMed  Google Scholar 

  76. Abdullah H, Heaney LG, Cosby SL, McGarvey LPA. Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity. Thorax. 2013;69:46–54.

    PubMed  Google Scholar 

  77. Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci. 2012;15:1063–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  78. Fryer AD, Stein LH, Nie Z, Curtis DE, Evans CM, Hodgson ST, et al. Neuronal eotaxin and the effects of CCR3 antagonist on airway hyperreactivity and M2 receptor dysfunction. J Clin Invest. 2006;116:228–36.

    PubMed Central  CAS  PubMed  Google Scholar 

  79. Ansel JC, Brown JR, Payan DG, Brown MA. Substance P selectively activates TNF-alpha gene expression in murine mast cells. J Immunol. 1993;150:4478–85.

    CAS  PubMed  Google Scholar 

  80. Ding W, Stohl LL, Wagner JA, Granstein RD. Calcitonin gene-related peptide biases Langerhans cells toward Th2-type immunity. J Immunol. 2008;181:6020–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  81. Cyphert JM, Kovarova M, Allen IC, Hartney JM, Murphy DL, Wess J, et al. Cooperation between mast cells and neurons is essential for antigen-mediated bronchoconstriction. J Immunol. 2009;182:7430–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Li WW, Guo TZ, Liang D, Shi X, Wei T, Kingery WS, et al. The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome. Pain. 2009;147:277–86.

    CAS  PubMed  Google Scholar 

  83. Veres TZ, Rochlitzer S, Shevchenko M, Fuchs B, Prenzler F, Nassenstein C, et al. Spatial interactions between dendritic cells and sensory nerves in allergic airway inflammation. Am J Respir Cell Mol Biol. 2007;37:553–61.

    CAS  PubMed  Google Scholar 

  84. Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, et al. Nociceptors are interleukin-1beta sensors. J Neurosci. 2008;28:14062–73.

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Zhang XC, Kainz V, Burstein R, Levy D. Tumor necrosis factor-α induces sensitization of meningeal nociceptors mediated via local COX and p38 MAP kinase actions. Pain. 2011;152:140–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  86. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, et al. Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;410:471–5.

    CAS  PubMed  Google Scholar 

  87. Liu T, Xu ZZ, Park CK, Berta T, Ji RR. Toll-like receptor 7 mediates pruritus. Nat Neurosci. 2010;13:1460–2.

    PubMed Central  CAS  PubMed  Google Scholar 

  88. Diogenes A, Ferraz CC, Akioian AN, Henry MA, Hargreavest KM. LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res. 2011;90:759–64.

    CAS  PubMed  Google Scholar 

  89. Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, et al. Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol. 2011;186:6417–26.

    PubMed Central  CAS  PubMed  Google Scholar 

  90. Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014;133:448–60.

    PubMed Central  CAS  PubMed  Google Scholar 

  91. Park CK, Xu ZZ, Berta T, Han Q, Chen G, Liu XJ, et al. Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron. 2014;82:47–54.

    CAS  PubMed  Google Scholar 

  92. Min H, Lee H, Lim H, Jang YH, Chung SJ, Lee CJ, et al. TLR4 enhances histamine-mediated pruritus by potentiating TRPV1 activity. Mol Brain. 2014;7:59.

    PubMed Central  PubMed  Google Scholar 

  93. Ferraz CC, Henry MA, Hargreaves KM, Diogenes A. Lipopolysaccharide from Porphyromonas gingivalis sensitizes capsaicin-sensitive nociceptors. J Endod. 2011;37:45–8.

    PubMed Central  PubMed  Google Scholar 

  94. Park E, Na HS, Song YR, Shin SY, Kim YM, Chung J. Activation of NLRP3 and AIM2 inflammasomes by Porphyromonas gingivalis infection. Infect Immun. 2014;82:112–23.

    PubMed Central  PubMed  Google Scholar 

  95. de Rivero Vaccari JP, Lotocki G, Marcillo AE, Dietrich WD, Keane RW. A molecular platform in neurons regulates inflammation after spinal cord injury. J Neurosci. 2008;28:3404–14.

    PubMed  Google Scholar 

  96. Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S, et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature. 2000;407:1011–5.

    CAS  PubMed  Google Scholar 

  97. Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L, Suzuki R, et al. Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature. 2000;407:1015–7.

    CAS  PubMed  Google Scholar 

  98. Lakshmi S, Joshi PG. Co-activation of P2Y2 receptor and TRPV channel by ATP: implications for ATP induced pain. Cell Mol Neurobiol. 2005;25:819–32.

    PubMed  Google Scholar 

  99. Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature. 2006;440:228–32.

    CAS  PubMed  Google Scholar 

  100. Trevisan G, Hoffmeister C, Rossato MF, Oliveira SM, Silva MA, Ineu RP, et al. Transient receptor potential ankyrin 1 receptor stimulation by hydrogen peroxide is critical to trigger pain during monosodium urate-induced inflammation in rodents. Arthritis Rheum. 2013;65:2984–95.

    CAS  PubMed  Google Scholar 

  101. Hoffmeister C, Silva MA, Rossato MF, Trevisan G, Oliveira SM, Guerra GP, et al. Participation of the TRPV1 receptor in the development of acute gout attacks. Rheumatology (Oxford). 2014;53:240–9.

    CAS  PubMed  Google Scholar 

  102. Andersson DA, Gentry C, Bevan S. TRPA1 has a key role in the somatic pro-nociceptive actions of hydrogen sulfide. PLoS One. 2012;7:e46917.

    PubMed Central  CAS  PubMed  Google Scholar 

  103. Zhang Z, Xu X, Ma J, Wu J, Wang Y, Zhou R, et al. Gene deletion of Gabarap enhances Nlrp3 inflammasome-dependent inflammatory responses. J Immunol. 2013;190:3517–24.

    CAS  PubMed  Google Scholar 

  104. Kummer JA, Broekhuizen R, Everett H, Agostini L, Kuijk L, Martinon F, et al. Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J Histochem Cytochem. 2007;55:443–52.

    CAS  PubMed  Google Scholar 

  105. Ramos HJ, Lanteri MC, Blahnik G, Negash A, Suthar MS, Brassil MM, et al. IL-1β signaling promotes CNS-intrinsic immune control of West Nile virus infection. PLoS Pathog. 2012;8:e1003039.

    PubMed Central  CAS  PubMed  Google Scholar 

  106. Karatas H, Erdener SE, Gursoy-Ozdemir Y, Lule S, Eren-Koçak E, Sen ZD, et al. Spreading depression triggers headache by activating neuronal Panx1 channels. Science. 2013;339:1092–5.

    CAS  PubMed  Google Scholar 

  107. Minkiewicz J, de Rivero Vaccari JP, Keane RW. Human astrocytes express a novel NLRP2 inflammasome. Glia. 2013;61:1113–21.

    PubMed  Google Scholar 

  108. Walsh JG, Muruve DA, Power C. Inflammasomes in the CNS. Nat Rev Neurosci. 2014;15:84–97.

    CAS  PubMed  Google Scholar 

  109. Allan SM. Pragmatic target discovery from novel gene to functionally defined drug target: the interleukin-1 story. Methods Mol Med. 2005;104:333–46.

    CAS  PubMed  Google Scholar 

  110. Alboni S, Cervia D, Sugama S, Conti B. Interleukin 18 in the CNS. J Neuroinflammation. 2010;7:9.

    PubMed Central  PubMed  Google Scholar 

  111. Morelli MB, Amantini C, Liberati S, Santoni M, Nabissi M. New potential therapeutic approaches in CNS neuropathies. CNS Neurol Disord Drug Targets. 2013;12:274–93.

    CAS  PubMed  Google Scholar 

  112. Takada Y, Numata T, Mori Y. Targeting TRPs in neurodegenerative disorders. Curr Top Med Chem. 2013;13:322–34.

    CAS  PubMed  Google Scholar 

  113. Hermosura MC, Garruto RM. TRPM7 and TRPM2 – candidate susceptibility genes for Western Pacific ALS and PD? Biochim Biophys Acta. 2007;1772:822–35.

    PubMed Central  CAS  PubMed  Google Scholar 

  114. Riccio A, Medhurst AD, Mattei C, Kelsell RE, Calver AR, Randall AD, et al. mRNA distribution analysis of human TRPC family in CNS and peripheral tissues. Brain Res Mol Brain Res. 2002;109:95–104.

    CAS  PubMed  Google Scholar 

  115. Tozzi A, Bengtson CP, Longone P, Carignani C, Fusco FR, Bernardi G, et al. Involvement of transient receptor potential-like channels in responses to mGluR-I activation in midbrain dopamine neurons. Eur J Neurosci. 2003;18:2133–45.

    PubMed  Google Scholar 

  116. de Lago E, de Miguel R, Lastres-Becker I, Ramos JA, Fernandez-Ruiz J. Involvement of vanilloid-like receptors in the effects of anandamide on motor behavior and nigrostriatal dopaminergic activity: in vivo and in vitro evidence. Brain Res. 2004;1007:152–9.

    PubMed  Google Scholar 

  117. Yamamoto S, Wajima T, Hara Y, Nishida M, Mori Y. Transient receptor potential channels in Alzheimer’s disease. Biochim Biophys Acta. 2007;1772:958–67.

    CAS  PubMed  Google Scholar 

  118. Lendman N, Jeong SY, Shin SY, Voronov SV, Serban G, Kang MS, et al. Presenilin mutations linked to familial Alzheimer’sdisease cause an imbalance in phosphatidylinositol 4,5-biphosphate metabolism. Proc Natl Acad Sci U S A. 2006;103:19524–9.

    Google Scholar 

  119. Lessard CB, Lussier MP, Cayouette S, Bourque G, Boulay G. The overexpression of presenilin2 and Alzheimer's-disease-linked presenilin-2 variants influences TRPC6-enhanced Ca2+ entry into HEK293 cells. Cell Signal. 2005;17:437–45.

    CAS  PubMed  Google Scholar 

  120. Fonfria E, Marshall IC, Boyfield I, Skaper SD, Hughes JP, Owen DE, et al. Amyloid beta-peptide(1–42) and hydrogen peroxide-induced toxicity are mediated by TRPM2 in rat primary striatal cultures. Neurochemistry. 2005;95:715–23.

    CAS  Google Scholar 

  121. Inoue K, Branigan D, Xiong ZG. Zinc-induced neurotoxicity mediated by transient receptor potential melastatin 7 channels. J Biol Chem. 2010;285:7430–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Weilinger NL, Maslieieva V, Bialecki J, Sridharan SS, Tang PL, Thompson RJ. Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction. Acta Pharmacol Sin. 2013;34:39–48.

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Ting JPY, Willingham SB, Bergstralh DT. NLRs at the intersection of cell death and Immunity. Nature Rev Immunol. 2008;8:372–9.

    CAS  Google Scholar 

  124. Zhong Z, Zhai Y, Liang S, Mori Y, Han R, Sutterwala FS, et al. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun. 2013;4:1611.

    PubMed Central  PubMed  Google Scholar 

  125. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008;9:857–65.

    PubMed Central  CAS  PubMed  Google Scholar 

  126. Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kaupplnen A. Amyloid-b oligomers set fire to inflammasomes and induce Alzheimer’s pathology. J Cell Mol Med. 2008;12:2255–62.

    CAS  PubMed  Google Scholar 

  127. Miller BA. The role of TRP channels in oxidative stress-induced cell death. J Membrane Biol. 2006;209:31–41.

    CAS  Google Scholar 

  128. Papatriantafyllou M. Innate immunity: inflammasome triggered by cell swelling. Nat Rev Immunol. 2012;12:742.

    PubMed  Google Scholar 

  129. Thilo F, Scholze A, Liu DY, Zidek W, Tepel M. Association of transient receptor potential canonical type 3 (TRPC3) channel transcripts with proinflammatory cytokines. Arch Biochem Biophys. 2008;471:57–62.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Giorgio Santoni.

Additional information

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

GS conceived the paper; CC, MBM, MS, MN and CA wrote the paper. All authors read and approved the final manuscript.

Rights and permissions

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Santoni, G., Cardinali, C., Morelli, M.B. et al. Danger- and pathogen-associated molecular patterns recognition by pattern-recognition receptors and ion channels of the transient receptor potential family triggers the inflammasome activation in immune cells and sensory neurons. J Neuroinflammation 12, 21 (2015). https://doi.org/10.1186/s12974-015-0239-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12974-015-0239-2

Keywords