Toll-like receptor 4 regulates subventricular zone proliferation and neuroblast migration after experimental stroke

Abstract

Ischemic stroke is one of the leading causes of death and disability with an urgent need for innovative therapies, especially targeting the chronic phase. New evidence has emerged showing that Toll-Like Receptor 4 (TLR4), a key mediator of brain damage after stroke, may be involved in brain repair by neurogenesis modulation. The aim of this study is to analyze the role of TLR4 in the different stages of neurogenesis initiated in the subventricular zone (SVZ) over time after stroke in mice. Wildtype and TLR4-deficient mice underwent experimental ischemia, and neural stem/progenitor cells (NSPCs) proliferation and migration were analyzed by using FACS analysis, fluorescence densitometry, RT-qPCR and in vitro assays. Our results show that both groups, wildtype and knock-out animals, present a similar pattern of bilateral cell proliferation at the SVZ, with a decrease in NSPCs proliferation in the acute phase of stroke. We also show that TLR4 activation, very likely mediated by ligands such as HMGB1 released to CSF after stroke, is necessary to keep an increased proliferation of NSCs as well as to promote differentiation from type C cells into neuroblasts promoting their migration. TLR4 activation was also implicated in earlier expression of SDF-1α and faster recovery of BDNF expression after stroke. These results support TLR4 as an important therapeutic target in the modulation of neurogenesis after stroke.