Extracellular CIRP Dysregulates Microglial Efferocytosis in Acute Ischemic Stroke via the TLR4/miR‐155/MafB Axis

ABSTRACT

Efferocytosis, the phagocytic clearance of dying cells, by microglia is crucial for limiting neuroinflammation and promoting resolution in ischemic stroke. Extracellular cold‐inducible RNA‐binding protein (eCIRP) is an inflammatory mediator that impairs macrophage bacterial phagocytosis in sepsis and radiation injury, but its role in microglial efferocytosis in ischemic stroke has not yet been studied. Using a transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke, this study demonstrated that eCIRP is released into the cerebrospinal fluid and microglial expression of the crucial efferocytic receptor MerTK decreases in tMCAO mice. CIRP deficiency significantly improved MerTK expression and microglial efferocytosis in tMCAO mice, reducing brain infarction, inflammation, neurological deficit, and survival in acute stroke. eCIRP induces pro‐inflammatory micro‐RNA 155 (miR‐155) via TLR4, which suppresses its target pro‐efferocytic transcription factor MAF bZIP (MafB), downregulating MerTK and the downstream cytoskeletal regulators, to impair microglial efferocytosis. Pharmacological blockade of eCIRP–TLR4 interaction using small peptide C23 attenuates miR‐155 induction, restores MerTK expression, rescues microglial efferocytosis, and improves outcomes in tMCAO mice. This study uncovers a previously unknown pathway through which eCIRP signaling impairs neuroprotective efferocytic microglial function in ischemic stroke, suggesting that targeting eCIRP may promote functional recovery after stroke.