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ULK1 Knockout Exacerbates Ischemia-Induced Microglial Dysfunction via TRAF6/NF-κB Signaling Pathway
Ye Xiong1, Zhuo Li Li2, Xiao Wan Wang2
1Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
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.
Insights
Unc-51-like autophagy activating kinase 1 (ULK1) regulates microglial activation and neuroinflammation in ischemic stroke. ULK1 deletion impairs myelin debris clearance, increasing pro-inflammatory responses via the TRAF6/NF-κB pathway.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia play a crucial role in the acute phase of ischemic stroke by migrating to infarct sites, mediating neuroinflammation, and clearing debris.
- The precise molecular mechanisms governing microglial activation and their inflammatory responses post-ischemic stroke are not fully understood.
Purpose of the Study:
- To investigate the role of unc-51-like autophagy activating kinase 1 (ULK1) in regulating microglial activation and neuroinflammation during ischemic stroke.
- To elucidate the signaling pathways involved in ULK1-mediated microglial responses.
Main Methods:
- Utilized a cortical photothrombotic ischemic stroke model in mice.
- Generated and analyzed unc-51-like autophagy activating kinase 1 (ULK1) knockout mice.
- Performed co-immunoprecipitation assays to identify protein interactions.
- Administered a tumor necrosis factor receptor-associated factor 6 (TRAF6) inhibitor in ischemic wild-type mice.
Main Results:
- ULK1 knockout mice displayed increased pro-inflammatory microglia and elevated pro-inflammatory mediators.
- ULK1 deletion impaired microglial phagocytosis of myelin debris, leading to myelin accumulation and heightened pro-inflammatory microglial activity.
- ULK1 was found to bind to tumor necrosis factor receptor-associated factor 6 (TRAF6) in primary microglia.
- Administration of a TRAF6 inhibitor modulated ULK1 and phosphorylated nuclear factor κ-B (p-NF-κB) protein levels in ischemic wild-type mice.
Conclusions:
- ULK1 plays a significant role in controlling microglial activation and neuroinflammation following ischemic stroke.
- ULK1 regulates these processes through interaction with TRAF6 and modulation of the TRAF6/NF-κB signaling pathway.
- Targeting ULK1 may offer a therapeutic strategy for managing neuroinflammation in ischemic stroke.
