Microglia/macrophages require vitamin D signaling to restrain neuroinflammation and brain injury in a murine ischemic stroke model

Vitamin D deficiency is associated with worse clinical outcomes after ischemic stroke; nevertheless, the pathophysiological mechanisms remain largely unexplored. In this study, we characterized the molecular mechanisms of how vitamin D signaling modulated stroke progression in male mouse ischemia-reperfusion stroke models. We found that vitamin D receptor (VDR) exhibited a predominant upregulation in peri-infarct microglia/macrophages following cerebral ischemia. Conditional Vdr inactivation in microglia/macrophages markedly augmented infarct volumes and neurological deficits. VDR-deficient microglia/macrophages exhibited a more primed proinflammatory phenotype with substantial secretion of TNF-alpha and IFN-gamma. These inflammatory cytokines further enhanced CXCL10 release from endothelial cells and blood-brain barrier disruption, and ultimately infiltration of peripheral T lymphocytes. Notably, blocking TNF-alpha and IFN-gamma significantly ameliorated stroke phenotypes in Vdr conditional knockout mice. Collectively, VDR signaling in microglia/macrophages plays a crucial role in restraining ischemia-elicited neuroinflammation and stroke progression. Our findings delineate a novel mechanism underlying the association between vitamin D deficiency and poor stroke outcomes, and underline the significance of maintaining a functional vitamin D signaling in the management of acute ischemic stroke.

Automated summary

In this study, the researchers investigated the molecular mechanisms of vitamin D signaling in regulating stroke progression. They found that the vitamin D receptor (VDR) was upregulated in microglia/macrophages following cerebral ischemia. Inactivation of VDR in these cells led to increased infarct volumes and neurological deficits. VDR-deficient microglia/macrophages exhibited a proinflammatory phenotype and released cytokines that promoted blood-brain barrier disruption and infiltration of peripheral T lymphocytes. Blocking these cytokines improved stroke outcomes in mice. These findings highlight the importance of maintaining functional vitamin D signaling in the management of acute ischemic stroke.