KAT2A knockdown induces microglia M2 polarization by succinylation of PRDX3 after traumatic brain injury

Neuroinflammation, a secondary injury following traumatic brain injury (TBI), is closely associated with microglial polarization. Emerging evidence suggests that succinylation plays a critical role in brain injury, yet its regulatory mechanisms remain unclear. Here, we investigated the role of KAT2A, a key succinyltransferase, in modulating microglial polarization.

Lipopolysaccharide (LPS) treated BV2 cell model and TBI mouse model were established. The expression of KAT2A was detected using quantitative real-time polymerase chain reaction (qPCR), western blot, and immunofluorescence. Microglia polarization was evaluated using qPCR to detect M1- and M2-associated marker levels. PRDX3 succinylation was analyzed using co-IP, immunoprecipitation, and western blot.

KAT2A was significantly upregulated in LPS-activated BV2 cells and microglia of the brain after TBI. Mechanistically, KAT2A interacted with PRDX3, and KAT2A knockdown inhibited PRDX3 succinylation at K84 site and enhanced PRDX3 stability. Functionally, KAT2A knockdown or PRDX3 overexpression suppressed M1 polarization and promoted M2 polarization. Notably, PRDX3 knockdown reversed the polarization effects induced by KAT2A suppression. Mutation of PRDX3 in the K84 site enhanced the effect of wild-type PRDX3 on polarization.

Silencing of KAT2A promotes microglia polarization from M1 to M2 phenotype by inhibiting the succinylation of PRDX3 at K84 site, suggesting a potential strategy for reducing neuroinflammation after TBI.