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

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

  • ACS Chem Neurosci. 2025 Aug 6;16(15):2978-2988. doi: 10.1021/acschemneuro.5c00284.
Ye Xiong 1,  Zhuo Li Li 2,  Xiao Wan Wang 2,  Ting Li 2,  Mai Yin Cui 3,  Min Min Wang 4,  Yan Qiong Fu 2,  Yu Zheng 2,  Wei Wei Xiang 2,  Yang Wang 2,  Bai Hui Chen 2
Affiliations

Affiliations

  • 1 Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
  • 2 Department of Histology and Embryology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China.
  • 3 Department of Rehabilitation and Traditional Chinese Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310052, P.R. China.
  • 4 Department of Gastrointestinal Surgery Nursing Unit, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
PMID: 40708226 DOI: 10.1021/acschemneuro.5c00284
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.

Keywords

TRAF6; ULK1; ischemic stroke; microglia; neuroinflammation; phagocytosis.

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