ULK1 Knockout Exacerbates Ischemia-Induced Microglial Dysfunction via TRAF6/NF-κB Signaling Pathway.

Abstract

Activated microglia rapidly migrate to the infarct site, mediate neuroinflammation, and phagocytose cell debris during the acute stage of ischemic stroke; however, the underlying mechanisms remain unclear. In this study, we utilized a cortical photothrombotic ischemic model and found that unc-51-like autophagy activating kinase 1 (ULK1) knockout mice exhibited increased pro-inflammatory microglia, along with upregulated levels of pro-inflammatory mediators. Further studies revealed that ULK1 deletion impaired the phagocytosis of myelin debris by microglia, thereby exacerbating myelin accumulation in the infarct zone and increasing pro-inflammatory phagocytic microglia. Moreover, coimmunoprecipitation results showed that ULK1 bound to tumor necrosis factor receptor-associated factor 6 (TRAF6) in primary microglia. Subsequently, we observed that the protein levels of ULK1 and phosphorylated nuclear factor κ-B (p-NF-κB) were regulated by the administration of the TRAF6 inhibitor C25-140 in ischemic wild-type (WT) mice. Overall, our study suggests that ULK1 regulates microglial activation and neuroinflammation via the TRAF6/NF-κB signaling pathway in ischemic stroke.