IL7R depletion mitigates neuroinflammation and ischemic stroke via AKT dephosphorylation dependent LCP1 suppression in mice.

Stroke remains a leading cause of death and long-term disability worldwide. After reperfusion following ischemic stroke, peripheral immune cells infiltrate the injured brain hemisphere and exacerbate secondary damage. Among these cells, monocytes are among the predominant population. In this study, we performed single-cell RNA sequencing of immune cells isolated from the brain 72 h after infarction and characterized the heterogeneity of brain infiltrating monocyte-derived macrophages. We identified an IL7R+ macrophage subset with high fatty-acid metabolism scores 3 days after ischemic stroke in mice. In vitro oxygen glucose deprivation cell model, Il7r expression was significantly increased, accompanied by upregulation of the PI3K-AKT pathway. IL7R knockdown decreased phosphorylated Akt and LCP1 levels, and LCP1 knockdown further reduced arachidonic acid, a key mediator of pro-inflammatory protein translation, as revealed by bulk RNA-seq and metabolomics analyses. Consistent with these in vitro results, IL7R depleted mice exhibited smaller infarct volumes and improved neurological function. Collectively, our findings provide mechanistic insight into how IL7R-pAKT-LCP1 signaling shapes immune-cell metabolism during stroke-induced neuroinflammation and suggest potential therapeutic opportunities targeting immunometabolic pathways in ischemic stroke.