Toll-like receptor 4 in CNS pathologies

Abstract

The responses of the brain to infection, ischemia and trauma share remarkable similarities. These and other conditions of the CNS coordinate an innate immune response marked by activation of microglia, the macrophage-like cells of the nervous system. An important contributor to microglial activation is toll-like receptor 4, a pathogen-associated molecular pattern receptor known to initiate an inflammatory cascade in response to various CNS stimuli. The present review traces new efforts to characterize and control toll-like receptor 4 in inflammatory etiologies of the nervous system.

Figure 1

The signaling pathways of TLR4. MyD88-dependant signaling is common to most TLRs including TLRs 1,2,4 (shown) and 5,6,7,8,9,11 (not shown). TRIF-dependant signaling results from TLR4 and TLR3 activation only. Note that TLR3 resides in endosomal vesicles, shown here responding to engulfed foreign RNA. The pentagon shapes denotes proteins that interact through a TIR domain. The TRAM adaptor (lime green) is exclusive to TLR4 and coordinates the TRIF response through TLR4’s TIR domain. TRIF-dependant signaling primarily results in IFN-β production (red adaptors), but the TRIF pathway also induces “late stage” NF-κB activation through RIP 1 (white) and TRAF 6 (seafoam green). The MyD88-dependant cascade initiates “early stage” NF-κB activation through the IKKs (IKKs α,β,λ) and/or the MAPK pathway, leading to proinflammatory cytokine expression and subsequent amplification through additional immune pathways.

Figure 2

Overall structure of the TLR4/MD-2 complex. (A) Side and top view of an m-shaped receptor multimer composed of two copies of the TLR4/MD-2 complex arranged symmetrically. (B) Close-up view of the LPS binding site on the TLR4/MD-2 interface. LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. The primary interface between TLR4 and MD-2 is formed before binding LPS, and the dimerization interface is induced upon LPS binding. (C) Molecular structure of LPS.