Elsevier

Experimental Neurology

Volume 258, August 2014, Pages 5-16
Experimental Neurology

Review
Pattern recognition receptors and central nervous system repair

https://doi.org/10.1016/j.expneurol.2014.01.001Get rights and content

Highlights

  • Describes the role of pattern recognition receptors in neuroinflammation

  • Describes the role of Toll-like receptors in inflammation after SCI

  • Discusses inflammasome activation after CNS injury and NLR/ALR contributions

Abstract

Pattern recognition receptors (PRRs) are part of the innate immune response and were originally discovered for their role in recognizing pathogens by ligating specific pathogen associated molecular patterns (PAMPs) expressed by microbes. Now the role of PRRs in sterile inflammation is also appreciated, responding to endogenous stimuli referred to as “damage associated molecular patterns” (DAMPs) instead of PAMPs. The main families of PRRs include Toll-like receptors (TLRs), Nod-like receptors (NLRs), RIG-like receptors (RLRs), AIM2-like receptors (ALRs), and C-type lectin receptors. Broad expression of these PRRs in the CNS and the release of DAMPs in and around sites of injury suggest an important role for these receptor families in mediating post-injury inflammation. Considerable data now show that PRRs are among the first responders to CNS injury and activation of these receptors on microglia, neurons, and astrocytes triggers an innate immune response in the brain and spinal cord. Here we discuss how the various PRR families are activated and can influence injury and repair processes following CNS injury.

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).

References (141)

  • L. Franchi et al.

    Differential requirement of P2X7 receptor and intracellular K + for caspase-1 activation induced by intracellular and extracellular bacteria

    J. Biol. Chem.

    (2007)
  • N.M. Green et al.

    Activation of autoreactive B cells by endogenous TLR7 and TLR3 RNA ligands

    J. Biol. Chem.

    (2012)
  • I. Grulova et al.

    The effect of hypothermia on sensory–motor function and tissue sparing after spinal cord injury

    Spine J.

    (2013)
  • C. Hashimoto et al.

    The Toll gene of Drosophila, required for dorsal–ventral embryonic polarity, appears to encode a transmembrane protein

    Cell

    (1988)
  • T. Horiguchi et al.

    Neuroprotection role of adenosine under hypothermia in the rat global ischemia involves inhibition of not dopamine release but delayed postischemic hypoperfusion

    Brain Res.

    (2002)
  • J. Husemann et al.

    Scavenger receptor class B type I (SR-BI) mediates adhesion of neonatal murine microglia to fibrillar beta-amyloid

    J. Neuroimmunol.

    (2001)
  • C.A. Janeway

    The immune system evolved to discriminate infectious nonself from noninfectious self

    Immunol. Today

    (1992)
  • T. Jin et al.

    Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor

    Immunity

    (2012)
  • K. Kariko et al.

    mRNA is an endogenous ligand for Toll-like receptor 3

    J. Biol. Chem.

    (2004)
  • T. Kinoshita et al.

    PYPAF3, a PYRIN-containing APAF-1-like protein, is a feedback regulator of caspase-1-dependent interleukin-1beta secretion

    J. Biol. Chem.

    (2005)
  • B. Lemaitre et al.

    The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults

    Cell

    (1996)
  • F. Martinon et al.

    The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta

    Mol. Cell

    (2002)
  • S.L. Masters

    Specific inflammasomes in complex diseases

    Clin. Immunol.

    (2013)
  • P. Matzinger

    An innate sense of danger

    Semin. Immunol.

    (1998)
  • N. Ohgami et al.

    Cd36, a member of the class b scavenger receptor family, as a receptor for advanced glycation end products

    J. Biol. Chem.

    (2001)
  • M. Okamoto et al.

    Constitutively active inflammasome in human melanoma cells mediating autoinflammation via caspase-1 processing and secretion of interleukin-1beta

    J. Biol. Chem.

    (2010)
  • Y. Okamura et al.

    The extra domain A of fibronectin activates Toll-like receptor 4

    J. Biol. Chem.

    (2001)
  • D.P. Abulafia et al.

    Inhibition of the inflammasome complex reduces the inflammatory response after thromboembolic stroke in mice

    J. Cereb. Blood Flow Metab.

    (2009)
  • S.E. Adamczak

    Molecular Recognition of DNA by the AIM2 Inflammasome Induces Neuronal Pyroptosis: Implications in Infection and Host Tissue Damage

    (2012)
  • S. Adamczak et al.

    Inflammasome proteins in cerebrospinal fluid of brain-injured patients as biomarkers of functional outcome: clinical article

    J. Neurosurg.

    (2012)
  • F. Ahmad et al.

    Hypothermia for acute spinal cord injury — a review

    World Neurosurg.

    (2013)
  • C. Bauer et al.

    Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome

    Gut

    (2010)
  • T.E. Bell et al.

    Mild hypothermia: an alternative to deep hypothermia for achieving neuroprotection

    J. Cardiovasc. Nurs.

    (1998)
  • L.P. Bernier

    Purinergic regulation of inflammasome activation after central nervous system injury

    J. Gen. Physiol.

    (2012)
  • M.E. Bianchi

    DAMPs, PAMPs and alarmins: all we need to know about danger

    J. Leukoc. Biol.

    (2007)
  • M.S. Brown et al.

    The scavenger cell pathway for lipoprotein degradation: specificity of the binding site that mediates the uptake of negatively-charged LDL by macrophages

    J. Supramol. Struct.

    (1980)
  • M. Bsibsi et al.

    Broad expression of Toll-like receptors in the human central nervous system

    J. Neuropathol. Exp. Neurol.

    (2002)
  • M. Bsibsi et al.

    Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators

    GLIA

    (2006)
  • M. Bsibsi et al.

    Toll-like receptors 2 and 3 agonists differentially affect oligodendrocyte survival, differentiation, and myelin membrane formation

    J. Neurosci. Res.

    (2012)
  • J.S. Cameron et al.

    Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals

    J. Neurosci.

    (2007)
  • K.S. Childs et al.

    LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA

    PLoS ONE

    (2013)
  • S. Cho et al.

    The class B scavenger receptor CD36 mediates free radical production and tissue injury in cerebral ischemia

    J. Neurosci.

    (2005)
  • C.C. da Costa et al.

    The role of the mouse macrophage scavenger receptor in myelin phagocytosis

    Eur. J. Neurosci.

    (1997)
  • D. Davalos et al.

    ATP mediates rapid microglial response to local brain injury in vivo

    Nat. Neurosci.

    (2005)
  • J.P. de Rivero Vaccari et al.

    A molecular platform in neurons regulates inflammation after spinal cord injury

    J. Neurosci. Off. J. Soc. Neurosci.

    (2008)
  • J.P. de Rivero Vaccari et al.

    Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury

    J. Cereb. Blood Flow Metab.

    (2009)
  • J.P. de Rivero Vaccari et al.

    P2X4 receptors influence inflammasome activation after spinal cord injury

    J. Neurosci. Off. J. Soc. Neurosci.

    (2012)
  • J.P. de Rivero Vaccari et al.

    Astrogliosis involves activation of retinoic acid-inducible gene-like signaling in the innate immune response after spinal cord injury

    Glia

    (2012)
  • J.P. de Rivero Vaccari et al.

    Mincle signaling contributes to the inflammatory response after traumatic brain injury

    J. Immunol.

    (2013)
  • Q.L. Deveraux et al.

    Cleavage of human inhibitor of apoptosis protein XIAP results in fragments with distinct specificities for caspases

    EMBO J.

    (1999)
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