Function and mechanism of toll-like receptors in cerebral ischemic tolerance: from preconditioning to treatment.

Peng-Fei Wang,Yan-Chun Wang,Xiao-Yi Xiong,Wei Duan,Jing Chen,Qing-Wu Yang

doi:10.1186/s12974-015-0301-0

Abstract

Increasing evidence suggests that toll-like receptors (TLRs) play an important role in cerebral ischemia-reperfusion injury. The endogenous ligands released from ischemic neurons activate the TLR signaling pathway, resulting in the production of a large number of inflammatory cytokines, thereby causing secondary inflammation damage following cerebral ischemia. However, the preconditioning for minor cerebral ischemia or the preconditioning with TLR ligands can reduce cerebral ischemic injury by regulating the TLR signaling pathway following ischemia in brain tissue (mainly, the inhibition of the TLR4/NF-κB signaling pathway and the enhancement of the interferon regulatory factor-dependent signaling), resulting in TLR ischemic tolerance. Additionally, recent studies found that postconditioning with TLR ligands after cerebral ischemia can also reduce ischemic damage through the regulation of the TLR signaling pathway, showing a significant therapeutic effect against cerebral ischemia. These studies suggest that the ischemic tolerance mediated by TLRs can serve as an important target for the prevention and treatment of cerebral ischemia. On the basis of describing the function and mechanism of TLRs in mediating cerebral ischemic damage, this review focuses on the mechanisms of cerebral ischemic tolerance induced by the preconditioning and postconditioning of TLRs and discusses the clinical application of TLRs for ischemic tolerance.

Highlights

Ischemic stroke, a current major disabling and killer disease worldwide, is characterized by a high incidence, morbidity, and disability rate
IRF3-deficient mice could not produce a protective effect against cerebral ischemia [60,63]. These results indicate that IRF3 plays an important role in the protective effect of TLR4 activation by LPS preconditioning against cerebral ischemia, and LPS preconditioning alters the toll-like receptors (TLRs) signaling pathway after stroke and has a protective effect against cerebral ischemia mainly through the TIR-domaincontaining adapter-inducing interferon-β (TRIF)/IRF3 signaling pathway (Figure 1B)
The protection of cerebral ischemia induced by LPS preconditioning disappeared in TRIF- and interferon regulatory factor (IRF)-knockout mice [60,81]. These results suggest that LPS preconditioning alters transcription in cells, inhibits the production of TNF-α and other proinflammatory factors induced by NF-κB, enhances the level of IFN-β induced by IRF3, alleviates the secondary inflammation after cerebral ischemia injury, and produces ischemic tolerance (Figure 1B)

Summary

Introduction

A current major disabling and killer disease worldwide, is characterized by a high incidence, morbidity, and disability rate. PolyIC preconditioning can activate the expression levels of TRIF and IRF3 in the ischemic brain tissue and increase the generation of IFN-β [68,71], which further supports the protective effect of the TRIF-IRF signaling pathway in cerebral ischemia (Figure 1D).

Results

Conclusion