STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis

TLDR

Innate immune activation drives the transition from nonalcoholic fatty liver to NASH, and the STING receptor senses released DNA to trigger such activation. The study investigated the role of STING in the progression of NASH in mice. NASH was induced in mice using methionine‑ and choline‑deficient and high‑fat diets, and hepatocyte mitochondrial DNA was shown to activate Kupffer cells via STING, with activation attenuated by STING deficiency or NF‑κB inhibition. STING deficiency reduced steatosis, fibrosis, and inflammation in both NASH models, improved metabolic parameters, and prevented DMXAA‑induced hepatic steatosis and inflammation, indicating that STING functions as an mtDNA sensor that triggers NF‑κB‑dependent inflammation in Kupffer cells during NASH.

Abstract

Innate immune activation contributes to the transition from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH). Stimulator of IFN genes (STING, also referred to Tmem173) is a universal receptor that recognizes released DNA and triggers innate immune activation. In this work, we investigated the role of STING in the progression of NASH in mice. Both methionine- and choline-deficient diet (MCD) and high-fat diet (HFD) were used to induce NASH in mice. Strikingly, STING deficiency attenuated steatosis, fibrosis, and inflammation in livers in both murine models of NASH. Additionally, STING deficiency increased fasting glucose levels in mice independently of insulin, but mitigated HFD-induced insulin resistance and weight gain and reduced levels of cholesterol, triglycerides, and LDL in serum; it also enhanced levels of HDL. The mitochondrial DNA (mtDNA) from hepatocytes of HFD-fed mice induced TNF-α and IL-6 expression in cultured Kupffer cells (KCs), which was attenuated by STING deficiency or pretreatment with BAY11-7082 (an NF-κB inhibitor). Finally, chronic exposure to 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a STING agonist) led to hepatic steatosis and inflammation in WT mice, but not in STING-deficient mice. We proposed that STING functions as an mtDNA sensor in the KCs of liver under lipid overload and induces NF-κB-dependent inflammation in NASH.