In this study, we revealed that CXCL5-CXCR2 signaling mediated a novel astrocyte-microglia circuit in CSVD, as astrocyte-derived CXCL5 aggravated WMI and cognitive decline via inhibiting microglial phagocytosis of myelin debris after binding to microglial CXCR2. The gene discussed is CXCL5; the disease is Mental deterioration.