4.7 Article

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

期刊

JOURNAL OF NEUROINFLAMMATION
卷 20, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s12974-023-02779-w

关键词

CKLF1; Microglia; Metabolic reprogramming; Immune tolerance; Ischemic stroke; Phagocytosis

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Ischemic stroke is associated with reactive microglia, but their exact role in stroke pathology is unknown. In this study, we demonstrated that chemokine like factor 1 (CKLF1) induces acute microglial inflammation and metabolic reprogramming. This reprogramming is mediated by the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-hypoxia inducible factor 1 alpha (HIF-1 alpha) signaling pathway. The loss of CKLF1 reverses the immunodeficiency of microglia, mitigating the long-term outcomes of ischemic stroke.
Ischemic stroke is characterized by the presence of reactive microglia. However, its precise involvement in stroke etiology is still unknown. We used metabolic profiling and showed that chemokine like factor 1 (CKLF1) causes acute microglial inflammation and metabolic reprogramming from oxidative phosphorylation to glycolysis, which was reliant on the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-hypoxia inducible factor 1 alpha (HIF-1 alpha) signaling pathway. Once activated, microglia enter a chronic tolerant state as a result of widespread energy metabolism abnormalities, which reduces immunological responses, including cytokine release and phagocytosis. Metabolically dysfunctional microglia were also found in mice using genome-wide RNA sequencing after chronic administration of CKLF1, and there was a decrease in the inflammatory response. Finally, we showed that the loss of CKLF1 reversed the defective immune response of microglia, as indicated by the maintenance its phagocytosis to neutrophils, thereby mitigating the long-term outcomes of ischemic stroke. Overall, CKLF1 plays a crucial role in the relationship between microglial metabolic status and immune function in stroke, which prepares a potential therapeutic strategy for ischemic stroke.

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