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