KAT3B Protects Against Septic Lung Injury by Regulating TSLP Succinylation and Macrophage Polarization

As a serious complication of sepsis, septic lung injury has a high rate of morbidity and mortality. However, the mechanism of septic lung injury remain unclear. The present study aims to explore the role of succinylation and KAT3B in the polarization of macrophages and the progression of septic lung injury. The cecal ligation and puncture (CLP) was used to establish the septic lung injury model. HE staining was performed to evaluate the lung injury. Raw264.7 cells were treated with lipopolysaccharide (LPS) to establish the cell model of septic lung injury. Macrophage polarization was evaluated by detecting M1 and M2 markers using quantitative real-time polymerase chain reaction and immunofluorescence. CO-IP was used to investigate the interaction between proteins. The experimental results indicated that KAT3B and the total succinylation was down-regulated in septic lung injury. LPS promoted M1 polarization and inhibited M2 polarization of Raw264.7 cells. KAT3B suppressed M1 polarization and promoted M2 polarization. Mechanistically, KAT3B desuccinylates TSLP at K239 and K292 site and promotes its stability. TSLP silencing reversed the effects of KAT3B. In vivo, KAT3B significantly reduced the lung injury and inflammation response of mice after CLP treatment. The present research unveiled the KAT3B acts as a protector against sepsis induced injury by mediating the succinylation of TLSP.