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PINEAU AND LACROIX
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