ReviewPattern recognition receptors and central nervous system repair
Introduction
The innate immune system senses potential pathogens and detects disruptions in tissue homeostasis by several receptor families. Collectively, these receptor families are referred to as pattern recognition receptors (PRRs) (Janeway, 1992). Unlike receptors involved in the adaptive immune response that are customized to recognize a specific protein or antigen, PRRs detect general “patterns” or sequences/structures commonly present on the surface of potential pathogens called pathogen associated molecular patterns (PAMPs). These receptors are highly conserved across multiple species and can be one of the first lines of defense against a possible infection. In addition to responding to PAMPs, PRRs also respond to “danger” signals or danger-associated molecular patterns (DAMPs). The “danger hypothesis” of immune system function was first proposed by Matzinger, 1994, Matzinger, 1998 in direct opposition to the idea that the immune system evolved to recognize self vs. non-self. This theory has grown as more endogenous ligands have been identified that are recognized by PRRs (Table 1). There are several sub-families of PRRs including Toll-like receptors (TLRs), Nod-like receptors (NLRs), C-type lectin receptors (CLRs), and RIG-like receptors (RLRs); each helps to orchestrate the innate immune response (Fig. 1). Some of these receptors are expressed on the cell surface (i.e. scavenger receptors and some TLRs) and facilitate surveillance of the extracellular environment while others are expressed intracellularly (NLRs, RLRs, some TLRs) and are activated by internalized inflammatory stimuli (e.g., DNA or RNA). Activation of these PRRs leads to production of inflammatory mediators that help remove pathogens or restore tissue homeostasis (Fig. 2). However, chronic activation of these receptors can cause inflammatory disease.
Section snippets
Pathogen associated molecular patterns and damage associated molecular patterns
Tissue injury, cellular stress, or disease induces the release of molecules that stimulate an innate immune response. Molecules released from pathogens are known as pathogen associated molecular patterns (PAMPs) whereas molecules of endogenous origin that are released from cells or from compartments within the cell into the cytoplasm are termed danger or damage associated molecular patterns (DAMPs) (Tang et al., 2012). DAMPs are released into the cytoplasm after central nervous system (CNS)
Toll-Like receptors
Toll-like receptors (TLRs) are homologues of the Toll receptor first identified in Drosophila (Medzhitov et al., 1997, Rock et al., 1998, Taguchi et al., 1996). In Drosophila, Toll plays a role during development in dorsal–ventral patterning and is important for anti-fungal immunity (Anderson et al., 1985a, Anderson et al., 1985b, Hashimoto et al., 1988, Lemaitre et al., 1996). The existence of human TLRs and their pivotal role in innate immune function was first discovered in the 1990s (
Toll-like receptors in CNS injury
Although TLRs have been traditionally characterized in response to pathogens, they also play an important role in regulating “sterile” inflammation. TLRs can orchestrate the innate immune response to trauma by recognizing DAMPs that are released from injured tissue. Several DAMPs are released after CNS injury and are known ligands for a range of TLRs (Table 1). These include HMGB1, heat-shock proteins (HSP60 and HSP70), degradation products of the ECM (hyaluronic acid, fibronectin) and nucleic
Conclusion
PRRs are a diverse group of receptor families that recognize heterogenous ligands, both self (DAMPs) and non-self (PAMPs), and elicit innate immune activation in response to injury or disease. Broad expression and injury-induced upregulation of these receptor families in the CNS by microglia, astrocytes, and neurons indicates a central role for PRRs in post-injury neurodegeneration and repair. In a complex injury site, such as a traumatic CNS injury, it is likely that these receptor families
Acknowledgments
The authors acknowledge support from the following: Craig H. Neilson 164246 (KAK) & 221346 (RWK); NIH NS059836 (RWK); NIH NS043246 (PGP); & the Poppleton Research Designated Chair (PGP).
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