Abstract
Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.
Highlights
Liver disease presents a globally recognized health threat with a mortality rate of 2 million deaths per year worldwide [1]
Mitochondrial DNA released from injured hepatocytes has been recognized as an endogenous damage-associated molecular patterns (DAMPs), which activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and promotes hepatic inflammation through release of cytokines in nonalcoholic steatohepatitis (NASH) [71], suggesting that cytosolic mitochondrial DNA (mtDNA) sensed by the cGAS-STING signaling is key to trigger innate immune response in NASH progression
A study in liver samples from 98 patients with nonalcoholic fatty liver disease (NAFLD) revealed that STING expression in Kupffer cells and monocyte-derived macrophages (MoMFs) was correlated with hepatic inflammation and fibrosis in human NAFLD [73]. These findings indicate that activation of the cGAS-STING pathway in macrophages is critical in NASH progression
Summary
Liver disease presents a globally recognized health threat with a mortality rate of 2 million deaths per year worldwide [1]. Numerous reports have identified the vital role of the cGASSTING signaling pathway in NASH progression by regulating innate immune activation Metabolic stress, such as a high-fat diet (HFD), could activate cGAS and the STING-IRF3-mediated inflammatory response [67]. Mitochondrial DNA (mtDNA) released from injured hepatocytes has been recognized as an endogenous DAMP, which activates the cGAS-STING pathway and promotes hepatic inflammation through release of cytokines in NASH [71], suggesting that cytosolic mtDNA sensed by the cGAS-STING signaling is key to trigger innate immune response in NASH progression. A study in liver samples from 98 patients with NAFLD revealed that STING expression in Kupffer cells and monocyte-derived macrophages (MoMFs) was correlated with hepatic inflammation and fibrosis in human NAFLD [73] These findings indicate that activation of the cGAS-STING pathway in macrophages is critical in NASH progression. Further studies will be needed to elucidate the coordination and orchestration of these IR-stressed cells regulated by the cGAS-STING pathway
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