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A breakdown of metabolic reprogramming in microglia induced by CKLF1 exacerbates immune tolerance in ischemic stroke
Wen-Yu Ma1, Qing-Lin Wu1, Sha-Sha Wang1
1Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China.
Abstract:
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 1α (HIF-1α) 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.
Insights
Chemokine like factor 1 (CKLF1) drives microglial inflammation and metabolic changes in ischemic stroke. Targeting CKLF1 may restore microglial immune function and mitigate stroke outcomes.
Area of Science:
- Neuroscience
- Immunology
- Metabolic Research
Background:
- Ischemic stroke involves reactive microglia, but their exact role remains unclear.
- Microglial metabolic reprogramming is implicated in stroke pathology.
Purpose of the Study:
- To investigate the role of chemokine like factor 1 (CKLF1) in microglial activation and metabolism during ischemic stroke.
- To elucidate the signaling pathways involved in CKLF1-induced microglial changes.
- To explore CKLF1 as a potential therapeutic target for ischemic stroke.
Main Methods:
- Metabolic profiling of microglia.
- Analysis of the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-hypoxia inducible factor 1α (HIF-1α) signaling pathway.
- Genome-wide RNA sequencing in mice after CKLF1 administration.
- Assessment of microglial phagocytosis and cytokine release.
Main Results:
- CKLF1 induces acute microglial inflammation and shifts metabolism from oxidative phosphorylation to glycolysis via the AMPK-mTOR-HIF-1α pathway.
- Activated microglia enter a chronic tolerant state with impaired immune responses (reduced cytokine release and phagocytosis) due to metabolic dysfunction.
- Chronic CKLF1 administration in mice led to metabolically dysfunctional microglia and a decreased inflammatory response.
- Loss of CKLF1 restored microglial immune function, including phagocytosis of neutrophils, mitigating long-term stroke outcomes.
Conclusions:
- CKLF1 is a key regulator linking microglial metabolic status and immune function in ischemic stroke.
- CKLF1-induced metabolic reprogramming contributes to immune tolerance in microglia during stroke.
- Modulating CKLF1 offers a potential therapeutic strategy for ischemic stroke by restoring microglial immune function.
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