Table 2.
Organ-specific diseases associated with cGAS–STING activation in humans or mice
| Disease names and/or affected tissues | Mouse models | Human diseases |
|---|---|---|
| ALS | Loss or blockade of STING rescued ALS phenotype In Prp-TDP-43Tg/+ mice133 | cGAMP detected in iPSC-derived motor neurons from patients with TARDBP mutations; increased cGAMP concentrations in spinal cord extracts from patients with ALS133 |
| PD | Lack of PINK1 or parkin led to oxidation of mtDNA and cGAS–STING activation135 | PINK1 or PRKN mutations associate with early-onset PD134 |
| AD | NAD+ supplementation reduced neuroinflammation by suppressing cGAS–STING137 | NA |
| Kidney disease | Cisplatin-induced tubular injury was attenuated by STING deficiency and inhibition5. Blocking STING trafficking from the ER improved glomerular pathology scores122 | cGAS and STING expression correlated with kidney fibrosis in patients with CKD7. cGAS–STING pathway implicated in diabetic kidney disease116 |
| Intestinal inflammation and microbiome |
STING deficiency or antagonism exacerbates gut inflammation142,144,146 STING contributes to gut microbial homeostasis143 Constitutive STING activation leads to dysbiosis and intestinal inflammation145 |
Increased STING levels in the colon of patients with ulcerative colitis145 |
| Familial chilblain lupus, UV skin responses, skin microbiome and acne |
Skin colonization with S. epidermidis led to cGAS–STING activation in keratinocytes140 UV light induces a IFN-I signature dependent on cGAS–STING106,107 |
Cutibacterium acnes associated with acne vulgaris stimulates IFN-I production in macrophages via cGAS–STING149 |
| Myocardial infarction, heart failure | cGAS- or STING-deficient mice are protected against myocardial infarction181,182. cGAS has an essential pathogenic role in pressure overload-induced heart failure182 | NA |
| Viral hepatitis | HBV evades immune sensing by inhibiting cGAS–STING expression and signalling183 | Decreased STING expression in peripheral blood of patients with HBV infection184 |
| NAFLD and NASH | Reduced liver injury in mice with impaired STING and high fat diet-induced NAFLD185. Macrophage activation via STING stimulates hepatocyte fat deposition and activates hepatic stellate cells186, possibly through sensing of mtDNA187 | Increased STING levels in livers of patients with NAFLD186,188 |
| ALD |
Ethanol-triggered ER stress causes activation of cGAS–STING58, STING-mediated apoptosis of hepatocytes189, and liver injury and fibrosis190 cGAMP transport through hepatic gap junctions amplifies tissue injury58 |
Increased cGAS–STING activation in the liver of patients with ALD58 |
| Obesity |
In DsbA-L KO, cGAS–STING activation suppresses thermogenesis and stimulates metabolic disorder117,191 High-fat diet causes metabolic stress and STING activation via mtDNA; STING deficiency partially prevented inflammation of adipose tissue, insulin resistance and obesity192 |
NA |
| Arthritis |
Sting1 loss protects Dnase2−/−Ifnar−/− mice from arthritis193 cGAS activation by self DNA causes arthritis in Dnase2−/−Ifnar1−/− mice65 TNF induces release of mtDNA, which activates cGAS; Cgas KO mice are protected from arthritis in the K/BxN arthritis model194 |
NA |
AD, Alzheimer disease; ALD, alcoholic liver disease; ALS, amyotrophic lateral sclerosis; cGAMP, 2′,3′-cyclic GMP–AMP; cGAS, cyclic GMP–AMP synthase; CKD, chronic kidney disease; ER, endoplasmic reticulum; HBV, hepatitis B virus; IFN-I, type I interferon; iPSCs, induced pluripotent stem cells; KO, knockout; mtDNA, mitochondrial DNA; NA, not available; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; PD, Parkinson disease; STING, stimulator of interferon genes; TNF, tumour necrosis factor; UV, ultraviolet. cGAS involvement in microbial infections is discussed in the main text.