CCDC50 Alleviates Cerebral Ischemia-Reperfusion Injury via Enhancing Autophagy to Inhibit STING/IRF3-Mediated...

Area of Science:

• Neuroscience
• Cell Biology
• Immunology

Background:

• Ischemia-reperfusion injury (IRI) significantly worsens outcomes in ischemic stroke.
• Multiple signaling pathways mediate the complex processes involved in cerebral IRI.
• The role of the autophagy receptor CCDC50 in cerebral IRI remains largely unexplored.

Purpose of the Study:

• To investigate the function of the novel autophagy receptor CCDC50 in cerebral IRI.
• To elucidate the molecular mechanisms underlying CCDC50's role in IRI.
• To identify potential therapeutic targets for mitigating stroke-related brain damage.

Main Methods:

• Established cellular oxygen-glucose deprivation/reoxygenation and middle cerebral artery occlusion (MCAO) animal models.
• Utilized quantitative real-time PCR, Western blot, immunofluorescence, and immunohistochemistry to assess protein expression and localization.
• Employed co-immunoprecipitation, ELISA, flow cytometry, and TTC staining to analyze protein interactions, inflammatory markers, microglial polarization, and infarct volume.

Main Results:

• LL37 directly binds and degrades CCDC50, disrupting CCDC50-STING interaction and activating the STING/IRF3 pathway.
• CCDC50 enhances autophagy, suppresses the STING/IRF3 pathway, and promotes M2 microglial polarization.
• CCDC50 alleviates neuronal damage by reducing inflammation and M1 microglial phenotype, an effect counteracted by LL37.

Conclusions:

• CCDC50 exerts a protective role in cerebral IRI by enhancing autophagy and suppressing the STING/IRF3 pathway.
• LL37 antagonizes CCDC50's protective effects through protein degradation, highlighting a novel regulatory axis.
• Targeting the CCDC50-LL37 interaction presents a promising therapeutic strategy for ischemic stroke.