A breakdown of metabolic reprogramming in microglia caused by CKLF1 exacerbates immune tolerance in the ischemic stroke

Abstract

Abstract Ischemic stroke has a prominent pathogenic hallmark called reactive microglia, which is a predictor of prognosis. The precise involvement of microglia in stroke etiology, however, is still unknown. We found that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis utilizing metabolic profiling, which was reliant on the AMPK-mTOR-HIF-1α signaling pathway. Microglia, once activated, entered a chronic tolerant state as a result of widespread energy metabolism abnormalities and therefore reduced immunological responses, including cytokine release and phagocytosis. It was also found metabolically dysfunctional microglia in the mice using genome-wide RNA sequencing by chronic administration of CKLF1 directly, as well as the decrease of inflammation response. Finally, we showed that loss of CKLF1 reversed the defective immune response of microglia, as manifested by kept its phagocytosis to neutrophils, thereby mitigating long term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial part in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke.