Xiaoyu Lin, Wanliang Du, Ruile Fang, Ying Ma, Yongjun Wang, Jialei Yang
Systemic inflammation is associated with worse outcomes after ischemic stroke, but the underlying mechanisms remain poorly understood. Microglial efferocytosis limits post-stroke inflammation and promotes recovery, whereas Wnt/β-catenin signaling has been implicated in neuroprotection and in regulation of CD36, a key efferocytotic receptor. Here, we investigated whether systemic inflammation is associated with alterations in microglial Wnt/β-catenin/CD36 axis and efferocytosis during ischemic injury. Mice were pretreated with lipopolysaccharide (LPS) before transient middle cerebral artery occlusion/reperfusion (tMCAO/R), and BV2 microglia were exposed to LPS before oxygen-glucose deprivation/reoxygenation (OGD/R). LPS pretreatment markedly increased infarct volume, worsened neurological deficits, and amplified post-ischemic neuroinflammatory responses. These effects were accompanied by enhanced microglial NF-κB signaling, increased p65/β-catenin interaction, and reduced nuclear β-catenin, consistent with suppression of Wnt/β-catenin signaling. Reduced CD36 expression and impaired microglial efferocytosis were observed in parallel. Notably, pharmacological activation of Wnt/β-catenin signaling with lithium chloride (LiCl) restored CD36 expression and microglial efferocytosis under LPS-pretreated conditions, and was accompanied by smaller infarcts, improved neurological function, and attenuated neuroinflammation. Collectively, these findings show that LPS pretreatment exacerbates ischemic stroke and is associated with enhanced microglial NF-κB signaling, dysregulation of the Wnt/β-catenin/CD36 axis, and impaired microglial efferocytosis. These results support defective microglial efferocytosis as a potential biological link between systemic inflammation and aggravated ischemic injury and identify Wnt/β-catenin signaling as a candidate pathway for further therapeutic investigation.