STING-dependent induction of lipid peroxidation mediates intestinal ischemia-reperfusion injury

Abstract

Stimulator of interferon genes (STING) is essential for the type I interferon response against DNA pathogens. Recent evidence has indicated that STING also plays a critical role in various diseases such as systemic lupus erythematous, nonalcoholic fatty liver disease, and cancer. However, the exact function and mechanism of STING in ischemia/reperfusion (I/R) injury, especially in the intestine, remains unknown. In the current study, we evaluated the contribution of STING to the intestinal I/R progression. The data indicate a robust STING activation, specifically in the reperfusion period, with the evidence of interferon response and NF-κB pathway activation. The intestinal I/R injury and distant organ damage was absent in STING−/- mice. Mechanically, this detrimental effect relies on excess level of lipid peroxidation, which was proved by the level of 4-hydroxynonenal (4-HNE) and the malondialdehyde (MDA). Additionally, bone marrow derived macrophage (BMDM) was stimulated with mtDNA or STING agonist showed a dose- and time-dependent lipid peroxidation and cell death, which could be reverse by STING−/- or pretreatment of lipid peroxidation inhibitor. Liproxstatin-1 could also ameliorate injury I/R induced multiple-organ damage. Similar results were also identified in the GSE96733 database, which indicated that STING activation was associated with the disbalance of lipid peroxidation and antioxidant system. Collectively, our results indicate a novel role for STING activation in the regulation of lipid peroxidation is closely associated with intestinal I/R injury, and that anti-lipid peroxidation is a unique and effective mechanistic approach for intestinal I/R injury and STING activation associated damage prevention and treatment.