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Review
. 2021 Apr 29:12:682736.
doi: 10.3389/fimmu.2021.682736. eCollection 2021.

The cGAS-STING Pathway: Novel Perspectives in Liver Diseases

Dongwei Xu  1   2 , Yizhu Tian  1 , Qiang Xia  2 , Bibo Ke  1
Affiliations
Review

The cGAS-STING Pathway: Novel Perspectives in Liver Diseases

Dongwei Xu et al. Front Immunol. .

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.

Keywords: DNA sensor; Innate immunity; cyclic GMPAMP synthase; inflammation; liver diseases; stimulator of interferon genes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The cytosolic DNA-sensing cGAS-STING pathway in innate immunity. Cyclic GMP-AMP synthase (cGAS) is a protein, which detects various cytosolic dsDNA, including viral DNA, damaged self-DNA released by dying cells, micronuclei, and mitochondrial origins. dsDNA activates cGAS via forming cGAS-dsDNA in 2:2 complexes. Mitochondrial damage and the release of mitochondrial DNA (mtDNA) in the cytosol also activates cGAS. The interactions of cGAS with DNA induce the formation of the liquid droplets through a phase transition, in which cGAS exerts its catalytic role to create the second messenger cGAMP that stimulates the stimulator of interferon genes (STING) at the endoplasmic reticulum (ER). STING then translocates from the ER to Golgi compartments and recruits kinases such as TANK-binding kinase 1 (TBK1) and IκB kinase (IKK), which in turn catalyzes the phosphorylation of IFN regulatory factor 3 (IRF3) and the nuclear factor-κB (NF-κB) inhibitor IκBα. Phosphorylated IRF3 translocates to the nucleus to activate transcription of genes encoding type I interferons and other inflammatory genes. IκBα phosphorylation accelerates nucleus translocation of NF-κB to promote transcription of target inflammatory cytokines, leading to activating inflammatory responses.
Figure 2
Figure 2
The cGAS-STING pathway in nonalcoholic fatty liver disease. A high-fat diet (HFD) causes steatosis, which induces mitochondrial stress damage in hepatocytes and subsequent releases of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA is recognized as an endogenous DAMP, which activates the cGAS-STING pathway and induces the IRF3 signaling to promote transcription of type I IFNs. Activation of the cGAS-STING pathway also induces the NF-κB signaling to produce proinflammatory cytokines, which triggers hepatic inflammatory responses. Moreover, proinflammatory cytokines activate macrophage function and produce TGF-β1, which activates hepatic stellate cells (HSCs) and promotes liver fibrosis in NASH.
Figure 3
Figure 3
The cGAS-STING pathway in alcohol-related liver disease. Alcohol-induced ER stress and mtDNA release activate the STING pathway. STING facilitates IRF3 phosphorylation by TBK1, which results in the translocation of IRF3 into the nucleus, where it induces transcription of type I IFNs. A gap junction intracellular communication pathway between alcohol-exposed hepatocytes and the neighboring parenchyma also contributes to the IRF3 activation by cGAS. Activation of IRF3 could trigger hepatocyte apoptosis, type I IFN response and produce proinflammatory cytokines, leading to hepatic inflammation and injury.
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