TNF leads to mtDNA release and cGAS/STING-dependent interferon responses that support inflammatory arthritis

Willemsen, Joschka; Neuhoff, Marie‐Therese; Hoyler, Thomas; Noir, Emma; Tessier, Clemence; Sarret, Sophie; Thorsen, Tara N.; Littlewood‐Evans, Amanda; Zhang, Juan; Hašan, Miloš; Rush, James S.; Guerini, Danilo; Siegel, Richard M.

doi:10.1016/j.celrep.2021.109977

Cited by 119 publications

(77 citation statements)

References 75 publications

(88 reference statements)

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“…Mitochondrial DNA (mtDNA) has been observed to activate proinflammatory responses in various diseases and pathological states, including AGS (Mustelin et al, 2019;Tumienė et al, 2017;West, 2017). Of note, TNFα, which we show to actively contribute to AGS astrocyte-mediated neurotoxicity, has very recently been shown to trigger mtDNA release and cGAS/STINGdependent IFN responses in inflammatory arthritis (Willemsen et al, 2021). It will be of interest to explore the contribution of mtDNA to AGS in our human CNS models of disease.…”

Section: Discussionmentioning

confidence: 75%

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

Giordano

Luciani

Gatto

et al. 2022

Journal of Experimental Medicine

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Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS.

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Section: Discussionmentioning

confidence: 75%

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

Giordano

Luciani

Gatto

et al. 2022

Journal of Experimental Medicine

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“…Since cGAS was reported to play roles in inflammatory responses in rheumatoid arthritis (RA) (Wang et al , 2015; Willemsen et al , 2021), we isolated peripheral blood mononuclear cells (PBMCs) from healthy people and rheumatoid arthritis (RA) patients and measured the expression of ZDHHC18 and cGAS. Both the mRNA levels of ZDHHC18 and cGAS were higher in RA patients, indicating the association between ZDHHC18 and cGAS in human cell systems (Appendix Fig S6G and H).…”

Section: Resultsmentioning

confidence: 99%

ZDHHC18 negatively regulates cGAS‐mediated innate immunity through palmitoylation

et al. 2022

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Double‐stranded DNA is recognized as a danger signal by cyclic guanosine monophosphate‐adenosine monophosphate synthase (cGAS), triggering innate immune responses. Palmitoylation is an important post‐translational modification (PTM) catalyzed by DHHC‐palmitoyl transferases, which participate in the regulation of diverse biological processes. However, whether palmitoylation regulates cGAS function has not yet been explored. Here, we found that palmitoylation of cGAS at C474 restricted its enzymatic activity in the presence of double‐stranded DNA. cGAS palmitoylation was catalyzed mainly by the palmitoyltransferase ZDHHC18 and double‐stranded DNA promoted this modification. Mechanistically, palmitoylation of cGAS reduced the interaction between cGAS and double‐stranded DNA, further inhibiting cGAS dimerization. Consistently, ZDHHC18 negatively regulated cGAS activation in human and mouse cell lines. In a more biologically relevant model system, Zdhhc18‐deficient mice were found to be resistant to infection by DNA viruses, in agreement with the observation that ZDHHC18 negatively regulated cGAS mediated innate immune responses in human and mouse primary cells. In summary, the negative role of ZDHHC18‐mediated cGAS palmitoylation may be a novel regulatory mechanism in the fine‐tuning of innate immunity.

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“…cGAS has an essential pathogenic role in pressure overload-induced heart failure 182 NA Viral hepatitis HBV evades immune sensing by inhibiting cGAS–STING expression and signalling 183 Decreased STING expression in peripheral blood of patients with HBV infection 184 NAFLD and NASH Reduced liver injury in mice with impaired STING and high fat diet-induced NAFLD 185 . Macrophage activation via STING stimulates hepatocyte fat deposition and activates hepatic stellate cells 186 , possibly through sensing of mtDNA 187 Increased STING levels in livers of patients with NAFLD 186 , 188 ALD Ethanol-triggered ER stress causes activation of cGAS–STING 58 , STING-mediated apoptosis of hepatocytes 189 , and liver injury and fibrosis 190 cGAMP transport through hepatic gap junctions amplifies tissue injury 58 Increased cGAS–STING activation in the liver of patients with ALD 58 Obesity In DsbA-L KO, cGAS–STING activation suppresses thermogenesis and stimulates metabolic disorder 117 , 191 High-fat diet causes metabolic stress and STING activation via mtDNA; STING deficiency partially prevented inflammation of adipose tissue, insulin resistance and obesity 192 NA Arthritis Sting1 loss protects Dnase2 −/− Ifnar −/− mice from arthritis 193 cGAS activation by self DNA causes arthritis in Dnase2 −/− Ifnar1 −/− mice 65 TNF induces release of mtDNA, which activates cGAS; Cgas KO mice are protected from arthritis in the K/BxN arthritis model 194 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.…”

Section: Cgas–sting In Diseasementioning

confidence: 99%

“…TNF induces release of mtDNA, which activates cGAS; Cgas KO mice are protected from arthritis in the K/BxN arthritis model 194 …”

Section: Cgas–sting In Diseasementioning

confidence: 99%

Role of the cGAS–STING pathway in systemic and organ-specific diseases

2022

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Cells are equipped with numerous sensors that recognize nucleic acids, which probably evolved for defence against viruses. Once triggered, these sensors stimulate the production of type I interferons and other cytokines that activate immune cells and promote an antiviral state. The evolutionary conserved enzyme cyclic GMP–AMP synthase (cGAS) is one of the most recently identified DNA sensors. Upon ligand engagement, cGAS dimerizes and synthesizes the dinucleotide second messenger 2′,3′-cyclic GMP–AMP (cGAMP), which binds to the endoplasmic reticulum protein stimulator of interferon genes (STING) with high affinity, thereby unleashing an inflammatory response. cGAS-binding DNA is not restricted by sequence and must only be >45 nucleotides in length; therefore, cGAS can also be stimulated by self genomic or mitochondrial DNA. This broad specificity probably explains why the cGAS–STING pathway has been implicated in a number of autoinflammatory, autoimmune and neurodegenerative diseases; this pathway might also be activated during acute and chronic kidney injury. Therapeutic manipulation of the cGAS–STING pathway, using synthetic cyclic dinucleotides or inhibitors of cGAMP metabolism, promises to enhance immune responses in cancer or viral infections. By contrast, inhibitors of cGAS or STING might be useful in diseases in which this pro-inflammatory pathway is chronically activated.

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TNF leads to mtDNA release and cGAS/STING-dependent interferon responses that support inflammatory arthritis

Cited by 119 publications

References 75 publications

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

ZDHHC18 negatively regulates cGAS‐mediated innate immunity through palmitoylation

Role of the cGAS–STING pathway in systemic and organ-specific diseases

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