The role of cGAS-STING signalling in liver diseases

Abstract

The recently identified novel cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) activates the downstream adaptor protein stimulator of interferon genes (STING) by catalysing the synthesis of cyclic GMP-AMP. This in turn initiates an innate immune response through the release of various cytokines, including type I interferon. Foreign DNA (microbial infection) or endogenous DNA (nuclear or mitochondrial leakage) can serve as cGAS ligands and lead to the activation of cGAS-STING signalling. Therefore, the cGAS-STING pathway plays essential roles in infectious diseases, sterile inflammation, tumours, and autoimmune diseases. In addition, cGAS-STING signalling affects the progression of liver inflammation through other mechanisms, such as autophagy and metabolism. In this review, we summarise recent advances in our understanding of the role of cGAS-STING signalling in the innate immune modulation of different liver diseases. Furthermore, we discuss the therapeutic potential of targeting the cGAS-STING pathway in the treatment of liver diseases.

Keywords: AIM2, absent in melanoma 2; ALD, alcohol-related liver disease; APCs, antigen-presenting cells; CDNs, cyclic dinucleotides; DAMPs, damage-associated molecular patterns; DCs, dendritic cells; ER, endoplasmic reticulum; GVHD, graft-versus-host disease; HCC, hepatocellular carcinoma; HSCs, hepatic stellate cells; IFN-I, type I interferon; IL, interleukin; IRF3, interferon regulatory factor 3; IRI, ischaemia refusion injury; KCs, Kupffer cells; LSECs, liver sinusoidal endothelial cells; MHC, major histocompatibility complex; NAFLD, non-alcoholic fatty liver disease; NK cells, natural killer cells; NPCs, non-parenchymal cells; PAMPs, pathogen-associated molecular patterns; PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein ligand-1; PPRs, pattern recognition receptors; SAVI, STING-associated vasculopathy with onset in infancy; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1; TGF-β1, transforming growth factor-β1; TLR, Toll-like receptor; TNF, tumour necrosis factor; XRCC, X-ray repair cross complementing; aHSCT, allogeneic haematopoietic stem cell transplantation; cGAMP, cyclic guanosine monophosphate-adenosine monophosphate; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; cGAS-STING signalling; dsDNA, double-strand DNA; hepatocellular carcinoma; innate immune response; liver injury; mTOR, mammalian target of rapamycin; mtDNA, mitochondrial DNA; nonalcoholic fatty liver disease; siRNA, small interfering RNA; ssRNA, single-stranded RNA; viral hepatitis.