STING contributes to the inflammation and proliferation of Staphylococcus aureus via mitochondrial reactive oxygen species-hypoxic inducible factor 1α axis in epithelial cells.

Abstract

Staphylococcus aureus infection poses a serious threat to the dairy industry and public health safety. The stimulator of interferon gene (STING) signaling pathway has been well established as effective in defending against viral infections. However, the role of STING is controversial during bacterial infections. Herein, we provide an insight into the role of STING during S. aureus infection. Our data revealed that the STING signaling pathway was activated in S. aureus-infected cells. In vitro investigations demonstrated that inhibiting STING reduced inflammation, hypoxia-inducible factor-1 alpha (HIF1α) expression, and mitochondrial reactive oxygen species (mROS) production. Interestingly, blocking HIF1α eliminated the escalation of inflammation associated with STING. Additionally, suppressing mROS production significantly reduced HIF1α expression and inflammation levels, while elevating mROS had the opposite effect. These results indicate that STING promoted inflammation through the mROS-HIF1α pathway. Given that glycolysis is driven by HIF1α, we investigated the role of glycolysis during infection. As expected, STING-elevated inflammation was linked with HIF1α-driven glycolysis. In terms of pathogenesis, STING contributed to S. aureus proliferation within cells and mouse mammary glands. Collectively, our findings demonstrate that STING facilitates infection via the mROS-HIF1α-glycolysis axis, highlighting its potential as a promising anti-inflammatory target.