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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.