Sting mutation attenuates acetaminophen-induced acute liver injury by limiting NLRP3 activation

Acetaminophen (N-acetyl-p-aminophenol; APAP), a widely used effective nonsteroidal anti-inflammatory drug, leads to acute liver injury at overdose worldwide. Evidence showed that the severity of liver injury associated with the subsequent involvement of inflammatory mediators and immune cells. The innate immune stimulator of interferon genes protein (STING) pathway was critical in modulating inflammation. Here, we show that STING was activated and inflammation was enhanced in the liver in APAP-overdosed C57BL/6J mice, and Sting mu-tation (Stinggt/gt) mice exhibited less liver damage. Multiplexing flow cytometry displayed that Sting mutation changed hepatic recruitment and replacement of macrophages/monocytes in APAP-overdosed mice, which was inclined to anti-inflammation. In addition, Sting mutation limited NLRP3 activation in the liver in APAP-overdosed mice, and inhibited the expression of inflammatory cytokines. Finally, MCC950, a potent and selective NLRP3 inhibitor, significantly ameliorated APAP-induced liver injury and inflammation. Besides, pretreatment of MCC950 in C57 mice resulted in changes of immune cells infiltration in the liver similar to Stinggt/gt mice. Our study revealed that STING played a crucial role in APAP-induced acute liver injury, possibly by maintaining liver immune cells homeostasis and inhibiting NLRP3 inflammasome activation, suggesting that inhibiting STING-NLRP3 pathway might be a potential therapeutic strategy for acute liver injury.

Automated summary

This study reveals the crucial role of STING in acetaminophen-induced acute liver injury and suggests that inhibiting the STING-NLRP3 pathway could be a potential therapeutic strategy for acute liver injury. The activation of STING and enhanced inflammation were observed in the liver of APAP-overdosed mice, and Sting mutation resulted in less liver damage and changes in immune cell infiltration. Moreover, Sting mutation limited NLRP3 activation and the expression of inflammatory cytokines. The NLRP3 inhibitor MCC950 also showed promising results in ameliorating APAP-induced liver injury and inflammation.