Annexin-A1 SUMOylation regulates microglial polarization after cerebral ischemia by modulating IKK alpha stability via selective autophagy

Annexin-A1 (ANXA1) has recently been proposed to play a role in microglial activation after brain ischemia, but the underlying mechanism remains poorly understood. Here, we demonstrated that ANXA1 is modified by SUMOylation, and SUMOylated ANXA1 could promote the beneficial phenotype polarization of microglia. Mechanistically, SUMOylated ANXA1 suppressed nuclear factor kappa B activation and the production of proinflammatory mediators. Further study revealed that SUMOylated ANXA1 targeted the I kappa B kinase (IKK) complex and selectively enhanced IKK alpha degradation. Simultaneously, we detected that SUMOylated ANXA1 facilitated the interaction between IKK alpha and NBR1 to promote IKK alpha degradation through selective autophagy. Further work revealed that the overexpression of SUMOylated ANXA1 in microglia/macrophages resulted in marked improvement in neurological function in a mouse model of cerebral ischemia. Collectively, our study demonstrates a previously unidentified mechanism whereby SUMOylated ANXA1 regulates microglial polarization and strongly indicates that up-regulation of ANXA1 SUMOylation in microglia may provide therapeutic benefits for cerebral ischemia.