Toll-like receptors in central nervous system glial inflammation and homeostasis - PubMed (original) (raw)

Review

Toll-like receptors in central nervous system glial inflammation and homeostasis

Tammy Kielian. J Neurosci Res. 2006 Apr.

Abstract

Toll-like receptors (TLRs) are a family of pattern-recognition receptors expressed on cells of the innate immune system that allow for the recognition of conserved structural motifs on a wide array of pathogens, referred to as pathogen-associated molecular patterns, as well as some endogenous molecules. The recent emergence of studies examining TLRs in the central nervous system (CNS) indicates that these receptors not only play a role in innate immunity in response to infectious diseases but may also participate in CNS autoimmunity, neurodegeneration, and tissue injury. This review summarizes the experimental evidence demonstrating a role for TLRs in the context of CNS inflammation in both infectious and noninfectious conditions.

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Figures

Fig. 1

Fig. 1

Signaling cascades initiated via TLR2- and TLR4-dependent activation. Engagement of TLR2 on the cell surface as a heterodimer with either TLR1 or TLR6 leads to the recruitment of the adaptor protein MyD88 and interaction with TIR-domain-containing adaptor protein (TIRAP) via death-domain interactions. Subsequently, IL-1-receptor-associated kinase (IRAK) and tumor necrosis factor-associated factor 6 (TRAF6) are recruited, leading to the phosphorylation and degradation of inhibitory-κB (IκB), allowing the nuclear translocation of NF-κB and subsequent induction of target genes such as tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1/CCL2). The adaptor molecule MD-2 is involved in TLR4-mediated activation, which can lead to the recruitment of either of two adaptor proteins: the MyD88-dependent pathway occurs as described for TLR2; however, an alternative pathway has recently been identified. Upon TLR4 activation, the adaptor protein TRIF-related adaptor molecule (TRAM) can be activated, which associates with TIR-domain-containing adaptor-inducing IFN-β (TRIF). This complex activates IKKε and interacts with TBK-1 to induce translocation of the IFN-inducible transcription factor interferon response factor-3 (IRF-3) to the nucleus, where it transcriptionally activates IFN-inducible genes, such as IFN-β and IFN-inducible protein of 10 kDa (IP-10). Figure adapted from Microbes and Infection, Vol. 6, Kaisho T. and Akira S., Pleiotropic function of Toll-like receptors, p. 1388–1394, 2004, with permission from Elsevier.

Fig. 2

Fig. 2

Potential roles of TLRs in the CNS response to infection and injury. Microglia and astrocytes respond to numerous PAMPs, including peptidoglycan (PGN; TLR2 agonist), double-stranded RNA (dsRNA; TLR3 agonist), lipopolysaccharide (LPS; TLR4 agonist), and unmethylated CpG oligodeoxynucleotides and/or bacterial DNA (CpG DNA; TLR9 agonist). The resultant effect of glial PAMP stimulation is the elaboration of a wide array of proinflammatory cytokines (including TNF-α, IL-1β, and IL-12), chemokines [including macrophage inflammatory protein-2 (MIP-2/CXCL2) and monocyte chemoattractant protein-1 (MCP-1)], and reactive oxygen/nitrogen species [ROI/RNI; including superoxide (O2−) and nitric oxide (NO)]. These proinflammatory mediators contribute to enhanced blood–brain barrier (BBB) permeability and the resultant influx of peripheral immune cells into the CNS parenchyma, the extent of which is dictated by the nature of the proinflammatory milieu. Endogenous TLR ligands may be released from injured cells within the CNS parenchyma that may serve to augment neuroinflammation further; however, their role in TLR-dependent glial activation remains to be determined. The outcome of this neuroinflammatory response (i.e., beneficial vs. detrimental) is unclear and likely depends on the context of the insult and duration of inflammation. (Figure adapted from Kielian, 2004a.)

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