Toll-like receptors in cerebral ischemic inflammatory injury

Abstract

Cerebral ischemia triggers acute inflammation, which has been associated with an increase in brain damage. The mechanisms that regulate the inflammatory response after cerebral ischemia are multifaceted. An important component of this response is the activation of the innate immune system. However, details of the role of the innate immune system within the complex array of mechanisms in cerebral ischemia remain unclear. There have been recent great strides in our understanding of the innate immune system, particularly in regard to the signaling mechanisms of Toll-like receptors (TLRs), whose primary role is the initial activation of immune cell responses. So far, few studies have examined the role of TLRs in cerebral ischemia. However, work with experimental models of ischemia suggests that TLRs are involved in the enhancement of cell damage following ischemia, and their absence is associated with lower infarct volumes. It may be possible that therapeutic targets could be designed to modulate activities of the innate immune system that would attenuate cerebral brain damage. Ischemic tolerance is a protective mechanism induced by a variety of preconditioning stimuli. Interpreting the molecular mechanism of ischemic tolerance will open investigative avenues into the treatment of cerebral ischemia. In this review, we discuss the critical role of TLRs in mediating cerebral ischemic injury. We also summarize evidence demonstrating that cerebral preconditioning downregulates pro-inflammatory TLR signaling, thus reducing the inflammation that exacerbates ischemic brain injury.

Figure 1

Toll-like receptor (TLR) signaling. TLRs are transmembrane proteins with a large extra-cellular domain containing a cytoplasmic Toll/IL-1 receptor (TIR) domain. All TLR family members, except TLR3, signal through the myeloid differentiation primary-response gene 88 (MyD88) to recruit downstream interleukin (IL)-1 receptor-associated kinases (IRAKs) and tumor necrosis factor (TNF)-receptor associated factor 6 (TRAF6). In TLR2 and TLR4 signaling, MyD88 adaptor-like protein (MAL) is required for recruiting MyD88 to their receptors, whereas in others such as TLR5, TLR7, TLR9, and TLR11, MAL is not required. TLR1 and TLR2 or TLR2 and TLR6 form heterodimers that signal through MAL/MyD88. TLR3 signals through the adaptor TIR-domain-containing adaptor protein inducing interferon (IFN)-β-mediated transcription-factor (Trif), which recruits and activates TNF receptor-associated factor-family member-associated NF-κB activator-binding kinase 1 (TBK1). In addition to the MAL/MyD88-dependent pathway, TLR4 can also signal through a MyD88-independent pathway that activates TBK1 via a Trif-related adaptor molecule (TRAM)-Trif-dependent mechanism. TLR5, TLR7/8, TLR9, and TLR11 use only MyD88 as its signaling adaptor. These kinases ultimately activate transcription factors such as nuclear factor-κB (NF-κB) and IFN regulatory factors (IRFs), which result in production of various cytokines such as TNF, IL, and IFNs.