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GLIA 57:351–361 (2009)

Endogenous Signals Initiating Inflammation in the Injured Nervous System ISABELLE PINEAU AND STEVE LACROIX* Department of Anatomy and Physiology, Laval University, Ste-Foy, Quebec, Canada

KEY WORDS ATP; cytokine; heat shock protein; macrophage; nucleotide; P2 receptor; sciatic nerve; spinal cord injury; toll-like receptor

ABSTRACT Glial cells are known to respond to a variety of neural injuries and play an important role in tissue damage and repair in the injured nervous system. This glial response, which is initially characterized by the expression of proinflammatory cytokines and chemokines and the attraction of microglial cells toward sites of injury, literally occurs within seconds to minutes of the injury. This suggests that signals that are endogenous to the nervous system are responsible for initiating neuroinflammation. In this review, we summarize the most recent advances made in the identification of these endogenous signals and describe the receptors and signaling pathways by which these ligands stimulate the production of cytokines and chemokines. Among these endogenous damage signals are ligands for toll-like receptors, including several heat shock proteins and extracellular matrix components, as well as self-derived RNA and DNA and associated proteins. Growing evidence also suggests that nucleotides released upon injury and acting through P2 receptors, such as ATP and UTP or their analogues, could serve as endogenous signals for the rapid response of glial cells. V 2008 Wiley-Liss, Inc. C

INTRODUCTION Although the chemokines, cytokines, and immune cells involved in neuroinflammation have been well characterized in the context of injury, surprisingly little is known regarding the molecules that initiate the inflammatory response. This is surprising because so many studies have suggested that the inflammatory response could either be beneficial or detrimental in the injured nervous system and considering the number of drugs that are currently being used or tested based on their pro- or anti-inflammatory properties. A better understanding of the molecules and receptors regulating the expression of chemokines and cytokines in the injured nervous system is therefore needed to more efficiently manipulate the neuroinflammatory response or some key aspects of it. Such knowledge would have important clinical benefits not only for traumatic injuries but also for neurodegenerative diseases, which almost all include an inflammatory component (Wyss-Coray and Mucke, 2002). C 2008 V

Wiley-Liss, Inc.

We recently demonstrated that CNS resident cells such as microglia are rapidly activated after spinal cord injury (SCI) and express mRNAs coding for proinflammatory chemokines and cytokines as early as 5 min after the insult (Pineau and Lacroix, 2007). Along these lines, two independent groups have shown using in vivo two-photon imaging that disruption of the blood–brain barrier or traumatic brain injury provokes an immediate response of microglial cells, highlighted by a switch from undirected to targeted movement of microglial processes toward the site of injury (Davalos et al., 2005; Nimmerjahn et al., 2005). Together, these results suggest that some forms of endogenous signals are almost immediately released after injury and trigger microglial responses such as attraction of microglial processes and de novo synthesis of chemokines and cytokines. A number of studies, including ours, have since focused on the identification of these endogenous ‘‘damage signals’’ and their receptors and signaling pathways using both in vitro and in vivo models of neural injury. The most likely candidates thus far are toll-like receptor (TLR) ligands, nucleotides, and glutamate, all of which were found to be released by glial and/or neuronal cells after injury (Fig. 1). Based on the ever increasing number of endogenous ‘‘damage signals’’ that have been identified over recent years in peripheral tissues in the context of injury [for review, (Zedler and Faist, 2006)], there is no doubt that additional ligands and receptors will also be characterized in the injured nervous system. This does not rule out the possibility that, under certain conditions of stress (e.g., energy deprivation), neural cells may become activated in the absence of such signals and release factors that may add to the inflammatory response. In this review, we focus on the endogenous molecules that initiate inflammation in the injured nervous system and the receptors and signaling pathways by which these ligands stimulate the production of chemokines/ cytokines (Fig. 2). Damage signals that have been identified and studied in non-nervous system tissues will not be discussed in this review. Similarly, the roles of the

Grant sponsors: Canadian Institutes of Health Research (CIHR), Natural Sciences and Engineering Research Council of Canada (NSERC). *Correspondence to: Dr. Steve Lacroix, CHUL Research Center and Laval University, 2705 Laurier Blvd., Ste-Foy, Quebec, Canada G1V 4G2. E-mail: steve.lacroix@crchul.ulaval.ca Received 20 May 2008; Accepted 1 August 2008 DOI 10.1002/glia.20763 Published online 19 September 2008 in Wiley InterScience (www.interscience. wiley.com).


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Fig. 1. Endogenous signals initiating inflammation in the injured nervous system. Schematic representation of the hypothetical cellular and molecular events responsible for the initiation of the inflammatory response after nervous system injury. Following injury, endogenous molecules such as heat shock proteins (HSPs), extracellular matrix (ECM) components, nucleotides, and glutamate are released almost immediately by damaged neural cells (represented with dashed/dotted

lines). These endogenous molecules are therefore in an ideal position to rapidly stimulate glial cells through toll-like receptors (TLRs), P2Y and P2X receptors (RCs), and glutamate receptors. Activation of these receptors results in the synthesis and release of proinflammatory chemokines and cytokines that control the recruitment and activation of both glial cells and blood-derived immune cells. BBB, blood–brain barrier.

inflammatory response in tissue damage and repair in the injured nervous system have been covered in a number of reviews and will not be discussed here (David and Lacroix, 2005; Donnelly and Popovich, 2008; Schwartz and Yoles, 2006).

(Hashimoto et al., 1988; Stein et al., 1991), the demonstration that TLRs may also mediate responses to nonpathogenic endogenous ligands in mammals came only recently (Akira et al., 2001). Several pieces of evidence have since contributed to demonstrate that many of these endogenous ligands are released in the context of injury and can trigger neuroinflammation. One of the first evidence linking TLRs with neuroinflammation and the production of chemokines/cytokines in the traumatically injured nervous system came from work done with Schwann cells. First, Karanth et al. (2006) found that molecules derived from nerve homogenates induced MCP-1 expression in primary Schwann cells, and that this effect was partially inhibited by TLR4 function-blocking antibodies. At about the same time, Lee et al. (2006) published results showing that Schwann cells treated with necrotic neuronal cells became activated and expressed proinflammatory genes

TOLL-LIKE RECEPTOR LIGANDS Toll-like receptors (TLRs) have been widely recognized for their essential role in innate immunity mainly because of their capacity to bind pathogen-associated molecular patterns and induce microbe clearance (Akira and Takeda, 2004; Medzhitov, 2001; Medzhitov and Janeway, 1997; Nguyen et al., 2002). Although earlier work done in Drosophila had previously established that activation of TLRs by endogenous ligands is essential for dorsoventral pattern formation during embryogenesis GLIA


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Fig. 2. Receptors and signaling pathways initiating neuroinflammation after injury. Schematic representation of the primary ligands, receptors, and signaling pathways that trigger the inflammatory response after nervous system injury. Stimulation of TLRs located on the cell-surface (e.g., TLR2 and TLR4) and endosomal (e.g., TLR3 and TLR7-9) membranes or P2 receptors (RCs) of the P2Y and P2X families by their respective ligands results in the activation of two majors signaling pathways: (1) the nuclear factor-jB (NF-jB) pathway, and (2) the mitogen-activated protein (MAP) kinase pathway. Note that stimulation of any of these receptors often leads to the simultaneous activation of both signaling pathways. Activation of the NF-jB pathway results in the phosphorylation and proteosomal degradation of IjB, which allows the release of transcription factors of the NF-jB family

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and their translocation as dimers into the cell nucleus. Binding of NFjB to DNA induces transcription of proinflammatory genes such as interleukin (IL)-1b and IL-6, among others. Activation of the MAP kinase cascade, in which signaling proceeds via sequential activation of MAP kinase kinase kinases (MAP-KKKs), MAP kinase kinases (MAPKKs), and MAP kinases of the ERK, JNK, and p38 families, results in the activation of transcription factors like activating protein-1 (AP-1), which controls the expression of chemokines/cytokines such as monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor (TNF). ECM, extracellular matrix; ERK, extracellular signal-regulated kinases; HSPs, heat shock proteins; JNK, C-Jun N-terminal kinases; MIP-1, macrophage inflammatory protein-1; p, phosphorylation site; p38, p38 MAP kinases.

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(TNF and iNOS) through TLR2 and TLR3 pathways. They further found that activation of nuclear factor kappa B (NF-jB) and mitogen-activated protein kinases (MAPK) p38 and c-Jun N-terminal kinase was involved in the production of chemokines/cytokines by activated Schwann cells. Several in vivo studies using models of neural injury have since established that TLR signaling is critical for neuroinflammation (Babcock et al., 2006; Boivin et al., 2007; Kigerl et al., 2007). These studies have shown that TLRs regulate chemokine/cytokine production, immune cell recruitment and/or activation, and even recovery of neurological functions in both the injured PNS and CNS. In the following sections, we provide an overview of the potential endogenous TLR ligands that have been found at sites of neural injury, including heat shock proteins (HSPs), extracellular matrix (ECM) components, and various other molecules.

Heat Shock Proteins Heat shock proteins (HSPs) are constitutively expressed intracellular molecular chaperones whose expression and release are increased when cells are exposed to stress (Lindquist, 1986; Tsan and Gao, 2004a,b). Recent studies have suggested that in addition to their role in protein folding, assembly, and transport, HSPs such as HSP60 and HSP70 could also modulate inflammation through their interactions with TLRs [for review, (Asea 2008; Takeda et al., 2003)]. Perhaps even more fascinating was the demonstration that not only microbial but also mammalian HSPs have potent immunostimulatory properties, which led to the suggestion that HSPs released by cells that are damaged by injury could initiate inflammation. By applying genomics and proteomics methods to axonal preparations purified from cultures of adult dorsal root ganglion sensory neurons obtained from rats that had previously received a sciatic nerve lesion, the Twiss laboratory recently demonstrated that several HSPs, including HSP60 and HSP70, are locally expressed by injured axons (Willis et al., 2005, 2007). This finding, combined with the fact that HSPs are released by CNS cells undergoing necrotic or apoptotic cell death (Lehnardt et al., 2008), clearly suggests that HSPs are in an ideal position to initiate neuroinflammation after traumatic injury. Although the idea that HSPs may serve as endogenous ligands of TLRs has been questioned because of potential cross-contamination of HSP preparations with the bacterial endotoxin lipopolysaccharide (LPS) (Gao and Tsan, 2003; Tsan and Gao, 2004a,b; Ye and Gan, 2007), Lehnardt et al., (2008) have recently excluded all LPS-related contamination issues by rigorously showing that denaturation or knock-down of HSP60 abrogates agonist activity, whereas incubation with a LPS antagonist does not. More specifically, their results showed that the release of HSP60 by necrotic or apoptotic CNS cells can activate TLR4 at the surface of microglia and mediate neuroinflammation through a MyD88-dependGLIA

ent pathway. On the basis of the experiments performed in mixed cultures, they also suggest that activation of TLR4 by HSP60 could mediate axonal loss and neuronal death in the injured CNS. This theory, however, has yet to be confirmed in vivo, as it contradicts findings from previous studies which showed that activation of TLRs is critical for recovery of neurological functions in animal models of neural injury (Boivin et al., 2007; Kigerl et al., 2007). When injected into the adult rodent CNS, at a dose reported to cause neuronal cell death in vitro (Lehnardt et al., 2008), the TLR4 ligand LPS failed to induce neurodegeneration despite stimulating robust activation of microglia, proinflammatory cytokine synthesis, and leukocyte infiltration (Andersson et al., 1992; Nadeau and Rivest, 2003; Soulet and Rivest, 2003). However, the injection of LPS to 7-day-old mice subjected to hypoxia-ischemia caused substantial axonal and neuronal loss (Lehnardt et al., 2003). In addition, the amount of brain damage and neurological deficits caused by focal cerebral ischemia were found to be significantly reduced in TLR2- and TLR4-deficient mice compared with wild-type littermates (Lehnardt et al., 2007; Tang et al., 2007). We interpret these findings to mean that neurons that become vulnerable as a result of injury or disease could be more susceptible to death in the presence of neuroinflammatory conditions. Yet the inflammatory response, or at least some aspects of it, is required for regeneration and repair of neural tissues. More studies will therefore be needed to determine which aspect of the inflammatory response is beneficial and which is detrimental, as inflammation clearly has a dual role in the injured nervous system.

Extracellular Matrix Components Growing evidence has suggested that, in addition to HSPs, TLRs can bind other nonpathogenic endogenous ligands, several of which fall in the category of extracellular matrix (ECM) components. It has been known for years that during inflammation associated with traumatic injury, proteolytic enzymes release biologically active soluble fragments from the ECM. What was unknown until recently, however, is that some of these ECM components can bind TLRs and activate innate immune responses [for review, see (Brunn and Platt, 2006)]. The ability of ECM components to activate immune cells is best documented for heparan sulfate (Johnson et al., 2002, 2004), hyaluronan-derived oligosaccharides (Jiang et al., 2005; Termeer et al., 2002), the extra domain A of fibronectin (Okamura et al., 2001), and biglycan (Schaefer et al., 2005), and there is a distinct possibility that other ECM components could also stimulate inflammation in a TLR-dependent fashion. One of the most fascinating discoveries from work on heparan sulfate and TLRs is perhaps the discovery that intact ECM apparently inhibits TLR4 activation and that ECM degradation by proteolytic enzymes not only relieves TLR4 inhibition but generates endogenous solu-


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ble heparan sulfate that stimulates the receptor (Brunn et al., 2005). Biglycan, which like heparan sulfate is a member of the proteoglycan family and is immunoactive only in its soluble form, was also found to stimulate the expression of proinflammatory chemokines/cytokines such as TNF and MIP-2 through activation of TLR4 and, to a lesser degree, TLR2 (Schaefer et al., 2005). Although biglycan and heparan sulfate proteoglycans are widely expressed in the nervous system (Bovolenta and Fernaud-Espinosa, 2000), it is unknown whether the immunoactive fragment of these molecules are released or secreted after neural injury. Historically, ECM components such as proteoglycans (e.g., chondroitin sulfate proteoglycans) have attracted considerable interest in the injured nervous system for their prominent roles in the formation of the glial scar and as inhibitors of axonal regeneration and plasticity (Fawcett and Asher, 1999; Galtrey and Fawcett, 2007; Hoke and Silver, 1996; Silver, 1994). Whether ECM components could have additional functions in injured neural tissues and contribute to neuroinflammation by stimulating the activation/recruitment of CNS resident cells (e.g., microglia) and blood-derived leukocytes remains an open question.

Other Endogenous TLR Ligands Recent studies have identified several other hostderived molecules that can be released upon cell damage or death and that were found to activate innate immunity through TLRs under certain non-infectious conditions. Among these are necrotic cells, which are recognized by TLR2 and TLR3 through yet undefined ligand(s) (Lee et al., 2006; Li et al., 2001). Growing evidence is also suggesting that host RNA, DNA, and RNAor DNA-associated proteins such as the DNA-binding protein high-mobility group box 1 protein (HMGB1) may be capable of stimulating TLRs (Barrat et al., 2005; Kariko et al., 2004; Kim et al., 2006; Leadbetter et al., 2002; Park et al., 2004, 2006; Scaffidi et al., 2002). All of these molecules have great relevance for neuroinflammation because they are endogenously present within all cells. However, what remains unclear regarding the potential activation of TLR3, TLR7, TLR8, and TLR9 by self-RNA and DNA is how these molecules could penetrate the cytoplasm of uninjured cells, as these receptors are located at the level of the endosome/lysosome membranes and therefore in an ideal position to recognize pathogen-derived nucleic acids (von Landenberg and Bauer, 2007). As suggested by Barrat et al. (2005), one possible way by which RNA and DNA may enter TLR-containing endosomal/lysosomal compartments is through receptor-mediated internalization processes. Alternatively, it is possible that the above-mentioned host-derived molecules may also signal through receptors other than TLRs, such as P2 receptors [see (Ni et al., 2002) and Fig. 2]. Like TLRs, NOD-like receptors (NLRs) and RIG-like receptors (RLRs) are two families of pathogen-detecting

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sensors playing an important role in innate immunity (Creagh and O’Neill, 2006). Although NLRs and RLRs were initially reported to mediate recognition of only bacterial and viral components (e.g., nucleic acids), recent work done in a pathogen-free trauma model has challenged this view. After showing the existence of a molecular platform termed the NAcht leucine-richrepeat protein 1 (NALP1) inflammasome, consisting of the NLR NALP1, caspase-1, caspase-11, ASC (apoptosisassociated speck-like protein containing a caspase-activating recruitment domain), and the X-linked inhibitor of apoptosis protein, in neurons of the normal rat spinal cord, de Rivero Vaccari et al. (2008) have elegantly demonstrated that SCI in these animals triggers activation of the multiprotein complex. Activation of the NALP1 inflammasome was shown to result in cleavage of caspase-1 and X-linked inhibitor of apoptosis protein and upregulation of caspase-11 and ASC, leading to maturation of bioactive IL-1b and IL-18. What remains unknown, however, is the identity of the endogenous molecule that has stimulated NALP1 inflammasome signaling after SCI and whether co-receptors such as TLRs were involved in this response. Because the NALP3 inflammasome has recently been shown to be activated by extracellular ATP (Mariathasan et al., 2006), it is tempting to believe that P2 receptors may also influence NLR signaling. Along these lines, we recently made the intriguing observation that the inflammatory response was not completely inhibited in MyD88-deficient mice, in experiments aimed at studying the importance of TLRs in chemokine/cytokine synthesis and leukocyte infiltration after peripheral nerve injury (Boivin et al., 2007). Together with the fact that the adaptor protein MyD88 is critical for signaling from all mammalian TLRs, except for TLR3 (Akira et al., 2006; Alexopoulou et al., 2001), these findings suggest that additional receptors and most likely other ligands are involved in the regulation of neuroinflammatory processes after injury (Fig. 2).

P2 RECEPTOR LIGANDS P2 receptors, also known as P2 purinoceptors, consist of two families of cell-surface receptors: a family of metabotropic receptors (P2Y; P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11–P2Y14) that belong to the G-protein coupled receptor (GPCR) superfamily, and a family of ionotropic receptors (P2X; P2X1–P2X7) [for reviews, see (Burnstock, 2007; North, 2002)]. They are mainly activated by purines and, in some cases, by pyrimidines, which explains why they have also been referred as nucleotide receptors. Although nucleotides such as ATP have long been recognized as key intracellular molecules, the idea that these molecules may also serve as extracellular messengers has drawn considerable opposition. However, there is now a strong scientific consensus that extracellular nucleotides and their P2 receptors are involved in many physiological and pathophysiological responses (Franke et al., 2006; Khakh and North, 2006). GLIA


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PINEAU AND LACROIX TABLE 1. Endogenous Molecules That May Initiate Neuroinflammation Through Toll-Like Receptors and P2 Receptors

Endogenous molecule

Receptor(s)

Heat shock proteins (HSPs) HSP60 HSP70 Gp96 HSP22 Extracellular matrix components Heparan sulfate Hyaluronan-derived oligosaccharide Biglycan Fibronectin extra domain A Necrotic cells RNA DNA (in the form of immune complexes) High mobility group box 1 protein (HMGB1) Nucleotides (e.g., ATP, ADP, UTP)

Proinflammatory mediators produced following receptor activation

TLR2, TLR4

TNF, NO

TLR2, TLR4 TLR2, TLR4 TLR4

TNF, IL-1b, IL-6, IL-12 TNF, IL-12 TNF, IL-6, IL-12

Lehnardt et al., 2008; Ohashi et al., 2000; Zanin-Zhorov et al., 2003 Asea et al., 2002; Vabulas et al., 2002a Vabulas et al., 2002b Roelofs et al., 2006

TLR4 TLR2, TLR4

TNF TNF, MIP-1a, MIP-2, KC

Brunn et al., 2005; Johnson et al., 2002, 2004 Jiang et al., 2005; Termeer et al., 2002

TLR2, TLR4 TLR4 TLR2, TLR3

TNF, MIP-2 MMP-9 TNF, IL-8, MIP-2, KC, MMP-3, iNOS IL-12, IFN-a

Schaefer et al., 2005 Okamura et al., 2001 Lee et al., 2006; Li et al., 2001

TLR3, TLR7, Unknown P2Y TLR9 TLR2, TLR4 P2X4 P2X7 P2Y2, P2Y4 P2Y6 P2Y12

IFN-a TNF, IL-1a, IL-1b, IL-6, IL-8, MIP-1a, MIP-1b, COX-2, iNOS TNF, IL-1b, MCP-1 LIF

Of particular interest to this review are studies which recently showed that signaling by P2 receptors could be implicated in the initiation of neuroinflammation in response to injury.

Nucleotides Evidence collected from many different studies suggests that nucleotides released after neural injury and acting through P2 receptors, such as ATP and UTP or their analogues, could serve as endogenous signals for the rapid response of glial cells. This was perhaps most convincingly demonstrated by two independent studies in which the chemotactic response of GFP-labeled microglia was studied in vivo using intravital two-photon microscopy (Davalos et al., 2005; Haynes et al., 2006). First, Davalos et al. (2005) reported that the rapid response of microglial processes toward the site of CNS injury can be mimicked by local injection of ATP into the brain. They further found that injection of an ATPhydrolyzing enzyme, apyrase, or P2Y receptor inhibitors at the site of injury significantly reduced the chemotactic response of microglia. It should be pointed out, however, that their data also raised the possibility that ATP may not be the endogenous chemoattractant responsible for the directional extension of microglial processes, although the presence of extracellular ATP was clearly sufficient to induce the observed microglial response. This affirmation is based on the finding that non-hydrolyzable ATP cannot attract microglial processes when coinjected with apyrase (Davalos et al., 2005). Interestingly, a previous study has shown that extracellular GLIA

References

Barrat et al., 2005; Kariko et al., 2004; Ni et al., 2002 Barrat et al., 2005; Leadbetter et al., 2002 Andersson et al., 2000; Kim et al., 2006; Park et al., 2004, 2006; Scaffidi et al., 2002 Tsuda et al., 2003; Ohsawa et al., 2007 Ferrari et al., 1997; Hide et al., 2000; Matute et al., 2007; Panenka et al., 2001; Solle et al., 2001; Wang et al., 2004 Yamakuni et al., 2002 Koizumi et al., 2007 Haynes et al., 2006

ADP, which can also be hydrolyzed by apyrase, is capable of inducing chemotaxis of cultured microglia through a P2Y receptor other than P2Y1 and P2Y2 (Honda et al., 2001). Furthermore, ATP is known to induce the expression and release of many cytokines and chemokines following activation of P2 receptors at the glial cell surface [see (Inoue, 2002) and Table 1]. Results to date have demonstrated that microglia express a wide variety of P2Y receptor subtypes, including P2Y1, P2Y2, P2Y6, and P2Y12 (Burnstock and Knight, 2004; Farber and Kettenmann, 2006). Of particular interest is the P2Y12 receptor, which has been detected in microglia but not in other CNS resident cell types or splenic macrophages using various methods such as microarrays, in situ hybridization, and immunohistochemistry (Bedard et al., 2007; Haynes et al., 2006; Kobayashi et al., 2008; Tozaki-Saitoh et al., 2008). Notably, the ability of microglia to migrate or extend their processes toward a source of nucleotides injected into the uninjured brain or sites of brain injury is severely compromised in P2Y12-deficient mice (Haynes et al., 2006). Inhibition of P2Y12 function suppressed the phosphorylation of p38 MAPK in spinal microglia and the development of neuropathic pain after partial sciatic nerve ligation (Kobayashi et al., 2008). Although the authors suggested that proinflammatory mediators such as cytokines may play a crucial role in these events, precisely how the activation of p38 MAPK through P2Y12 in microglia might cause pain hypersensitivity is unknown at the moment. An important finding of the study of Haynes et al., however, is that the chemotactic responses of microglia toward sites of CNS injury were not completely abolished but rather delayed in P2Y12-


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knockout mice when compared with wild-type littermates. This once again indicates that other signaling mechanisms could be involved in the early response of microglia after injury. Another P2Y receptor involved in microglial responses is P2Y6. Contrary to P2Y12, the activation of P2Y6 by extracellular UDP (released as UTP by damaged neural cells) is not involved in cell motility but rather coupled to a different microglial response, namely phagocytosis (Koizumi et al., 2007). In addition to the P2Y receptors listed earlier, microglia also express functional P2X receptors such as P2X4 and P2X7 (Koizumi et al., 2007; Tsuda et al., 2003). Like P2Y12 receptors, P2X4 receptors are expressed exclusively by microglia in the CNS and are also involved in ATP-induced microglial chemotaxis (Ohsawa et al., 2007; Tsuda et al., 2003). Intrathecal administration of pharmacological blockers of P2X4 receptors to rats was reported to repress tactile allodynia after peripheral nerve injury (Tsuda et al., 2003). Conversely, intrathecal injection of microglia that had been preincubated with ATP at 50 lM was sufficient to produce tactile allodynia in uninjured animals. ATP at 50 lM was reported to activate P2X4 receptors preferentially, but not P2X7 receptors, in primary cultures of microglia. However, whether such pretreatment conditions could have stimulated other types of microglial receptors, including P2Y receptors, was not investigated in this particular study (Tsuda et al., 2003). More recently, the De Koninck laboratory reported that the release of brain-derived neurotrophic factor by microglia following stimulation of P2X receptors by ATP is a key mechanism of pain hypersensitivity (Coull et al., 2005). The P2X7 receptor is another ligand-gated ion channel for which a role in inflammation has been reported (Labasi et al., 2002; Solle et al., 2001). ATP is believed to be the main endogenous ligand of P2X7 receptors (Burnstock, 2007). When stimulated with ATP, macrophages lacking P2X7 receptors are unable to release mature IL-1b (Solle et al., 2001). When challenged with both ATP and LPS, however, P2X7-deficient macrophages are capable of generating the cell-associated proIL-1b but not the mature extracellular form. This suggests that activation of P2X7 receptors by extracellular ATP can provide a signal that leads to posttranslational processing of IL-1b. This finding is particularly meaningful considering the capacity of recombinant IL-1b to stimulate the production of other cytokines and chemokines, such as TNF, MCP-1, and MIP-1, when introduced into the CNS (Perrin et al., 2005). In the nervous system, P2X7 receptors are constitutively expressed by microglia, astrocytes, oligodendrocytes, Schwann cells, and neurons (Choi et al., 2007; Duan et al., 2003; Grafe et al., 1999; Matute et al., 2007; Panenka et al., 2001; Wang et al., 2004). Pharmacological blockade of P2X7 receptors in cultured microglia was found to prevent LPS-induced expression of mRNAs coding for several proinflammatory cytokines, including IL1b, TNF, and IL-6 (Choi et al., 2007). When administered intracerebroventricularly to rats that received a single injection of LPS (5 lg) into the striatum, the

same treatment partially attenuated the activation of NF-jB and p38 MAPK signaling pathways in microglia and increased neuronal survival. In astrocyte cultures, treatment with an agonist of P2X7 receptors activated MAPK pathways and increased MCP-1 expression (Panenka et al., 2001). Furthermore, this study showed that treatment with a wide-spectrum antagonist of P2 receptors, suramin, attenuated MCP-1 expression in response to corticectomy. The latter result should be interpreted with care, however, as suramin has been reported to affect not only various subtypes of P2X and P2Y receptors (Anderson and Nedergaard, 2006; Burnstock, 2007), but also glutamate and GABA receptors (Nakazawa et al., 1995; Suzuki et al., 2004). As reviewed elsewhere, glial cells express neurotransmitter receptors such as glutamate and GABA receptors, and activation of these receptors appears to participate in the control of neuroinflammatory conditions (Pocock and Kettenmann, 2007). Evidence obtained recently suggests that ATP-induced activation of P2X7 receptors could also be implicated in damage of neural cells during CNS injuries and diseases (Matute et al., 2007; Wang et al., 2004). First, Wang et al. (2004) reported that P2X7 receptor inhibition reduces secondary neuronal loss and improves locomotor recovery after SCI. In vivo bioluminescence imaging of SCI rats revealed the presence of high levels of ATP in spinal cord areas surrounding the lesion, but not at the site of damage, during the first few hours following injury. Further analyses confirmed that areas of high ATP release were associated with increased apoptosis of neurons and oligodendrocytes. When agonists specific for each of the P2X receptors were injected into the spinal cord of uninjured rats, only the P2X7-specific agonist was able to induce cell death. In another study, Matute et al. (2007), reported that ATP signaling through P2X7 is at least partly responsible for oligodendrocyte death during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Like Wang et al. (2004), they observed that infusion of an agonist selective for P2X7 in the CNS (optic nerve) was sufficient by itself to trigger oligodendrocyte excitotoxicity. Administration of P2X7 antagonists to EAE mice was also found to reduce demyelination and modestly improve neurological functions. Finally, the study showed that P2X7 expression is upregulated in normally appearing optic nerves of MS patients when compared with nerves of healthy subjects, supporting once again the idea that activation of these receptors may contribute to loss of neural cells in the injured/diseased CNS. Future studies should help determine the true therapeutic potential of using pharmacological blockers of P2 receptors for the treatment of complex neural injuries and diseases in humans.

OTHER ENDOGENOUS DAMAGE SIGNALS Glutamate As mentioned earlier, ample evidence now supports the notion that neurotransmitters such as glutamate GLIA


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could be involved in the initiation and control of the neuroinflammatory response. Because most of this evidence has already been documented elsewhere [see (Pocock and Kettenmann, 2007)], only the most recent findings in this field of research will be briefly reviewed here. Like P2 receptors, glutamate receptors consist of two families of cell-surface receptors: a family of ionotropic receptors (iGluRs; NMDA, AMPA, kainate), and a family of metabotropic receptors (mGluRs; mGluR1-mGluR8) that belong to the GPCR superfamily. mGluRs are subdivided into three groups: Group I (mGluR1 and mGluR5), Group II (mGluR2 and mGluR3), and Group III (mGluR4, -6, -7, and -8). Although glial cells express different subtypes of iGluRs and mGluRs [for reviews, see (Kettenmann and Steinhauser, 2005; Matute et al., 2006; Pocock and Kettenmann, 2007; Verkhratsky and Steinhauser, 2000)], a role in neuroinflammation has been mostly described for mGluRs. Notably, Kaushal and Schlichter have recently shown using an in vitro model of the ischemic penumbra that neurons deprived in oxygen and glucose release glutamate, which in turn can activate NF-jB pathways in microglia through Group II mGluRs (Kaushal and Schlichter, 2008). Activation of NF-jB pathways in microglia was further shown to result in the production and release of TNF. When healthy neurons in culture were exposed to glutamate-activated microglia, neurotoxicity was observed in a TNF/TNFR1-dependent fashion. These results are consistent with previous observations made by the Pocock laboratory (Taylor et al., 2002, 2005), therefore strengthening the idea that glutamate released by unhealthy or damaged neurons might be another endogenous signal that can trigger neuroinflammation. Still, the exact consequences of glutamate-mediated inflammation remain poorly understood and controversial, with evidence supporting both beneficial and detrimental effects in the nervous system. One example of this controversy are earlier studies which reported that activation of Group II mGluRs reduces neuronal death and improves neurological recovery using two different models of CNS insults (Allen et al., 1999). Whether inflammatory cells and molecules were implicated in these effects was not investigated, however, in these studies. These results illustrate the complexity of working with animal models in which different cell types expressing different receptor subtypes can intervene. Such complexity is perhaps best illustrated by results generated from DNA microarray experiments in organotypic hippocampal preparations protected from NMDA-induced neurotoxicity by pretreatment with an agonist of Group 1 mGluR (Baskys and Blaabjerg, 2005; Blaabjerg et al., 2003). Treatment with the Group 1 mGluR agonist resulted in a complex pattern of gene expression with the regulation of several genes associated with diverse functions, including downregulation of genes associated with inflammatory processes and cell death. Dissecting out the transduction signals that are activated downstream of these GluRs could be a good starting point to unravel the role of these receptors in neuroinflammation and loss/recovery of neurological functions. GLIA

Alarmins Alarmins constitute a large family of endogenous signals capable of stimulating the immune response after tissue injury (Oppenheim and Yang, 2005). Among them are the DNA-binding protein HMGB1 and different families of proteins, including defensins, cathelicidins, and eosinophil-derived neurotoxins, which can be released from storage compartments by injurious stimuli. One particularity of the alarmins is that they not only have the capacity to activate cells and stimulate the production and release of chemokines and cytokines, but also have chemoattracting effects on various subpopulations of immune cells. Evidence to date suggests that the activating abilities of alarmins are mediated through receptors such as TLRs and nucleotide receptors, whereas their chemotactic effects are mediated by chemokine receptors and GPCRs (Oppenheim and Yang, 2005). Future studies should help determine whether alarmins are released in the nervous system upon injury and identify the exact receptors used by these molecules to induce inflammation.

CONCLUSION AND FUTURE PROSPECTS Progress made in our understanding of how damaged tissue orchestrates inflammation has allowed the identification of several endogenous molecules that are rapidly liberated upon injury and can stimulate the release of proinflammatory chemokines and cytokines. This has recently led to the identification of at least some of the receptors for these endogenous damage molecules and the partial characterization of the signaling pathways activated downstream of these receptors (Fig. 2). As we are only beginning to understand the molecular mechanisms initiating inflammation in the injured and diseased nervous system, more endogenous damage signals will probably be discovered in the future. In fact, this is almost a certainty considering the recent advances made in this field, especially in work dealing with non-nervous system tissues and cells where new endogenous mediators of innate immunity have just recently been identified. Because receptors of endogenous damage signals appear to be activated by a wide spectrum of ligands, as is the case for TLRs and P2 receptors, and because identifying all binding partners of these receptors will probably require years of research, it seems appropriate to start examining the importance and contribution of the receptors that have already been identified, individually or as a group, for neuroinflammation in in vivo models of CNS injury and disease. Also, more efforts should be directed toward understanding the role of the neuroinflammatory response induced by these signals in damage and repair of neural tissue using the same models. Gaining such knowledge will be critical before proceeding to any assessment of the therapeutic potential of stimulating or blocking receptors of endogenous damage signal for the treatment of traumatic nervous system injuries and neurodegenerative diseases.


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ACKNOWLEDGMENTS The authors thank Marc-Andr e Laniel for his help in editing this manuscript. The work done in SL’s laboratory is supported by a career award from the Rx&D Health Research Foundation and the CIHR.

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