The role of Toll-like receptors in CNS response to microbial challenge

Abstract

The recent discovery of the family of Toll-like receptors has vastly expanded our understanding of the mechanisms by which the innate immune system recognizes and responds to a wide variety of microbial and endogenous pathogens. Toll-like receptors are transmembrane proteins that upon ligation with their cognate ligands trigger the production of cytokines, enzymes and other inflammatory agents. In the CNS Toll-like receptors are expressed predominantly by glial cells. In particular, the vastly abundant astrocytes are likely to be the major contributors to inflammatory responses within the CNS. Studies of the murine brain abscess model revealed that Toll-like receptor 2 plays a pivotal role in the generation of immune responses to Staphylococcus aureus. Although Toll-like receptor signaling is essential in antimicrobial defense, it may also lead to bystander injury of CNS tissue.

Fig. 1

Two branches of TLR downstream signaling. All TLRs with the exception of TLR3 signal through the myeloid differentiation factor 88 (MyD88)-dependent pathway (red arrows). Upon ligand binding the cytoplasmic domain of TLRs, called the TIR domain, associates with an adaptor molecule, MyD88. The complex recruits IL-1 receptor-associated kinase (IRAK) that undergoes autophosphorylation, dissociates from the TLR signaling complex, and associates with TNF receptor-associated factor 6 (TRAF6). This association leads to the activation of NF-κB and MAPK that, in turn, up-regulate the expression of a core set of pro-inflammatory cytokine genes. In addition to this MyD88-dependent pathway, TLR3 and TLR4 signal in a MyD88-independent manner (blue arrows) through the recruitment of another adapter molecule, the TIR domain-containing adaptor inducing IFNβ (TRIF). TRIF activates the interferon regulatory factor (IRF)-3 that up-regulates the expression of the IFNβ gene. TRIF also interacts with TRAF6 leading to the activation of NF-κB and MAPK, and consequently to up-regulated expression of cytokine genes.