Type-1 interferon-dependent and -independent mechanisms in cyclic GMP–AMP synthase–stimulator of interferon genes-driven auto-inflammation

Gao, Kevin Mj; Marshak‐Rothstein, Ann; Fitzgerald, Katherine A.

doi:10.1016/j.coi.2022.102280

Cited by 6 publications

(3 citation statements)

References 72 publications

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“…The results are consistent with previous finding that the impaired CD4 T cell proliferation by the SAVI(V155M) mutant could be rescued by the addition of the HAQ allele in vitro 23 . Besides SAVI, STING has been increasingly implicated in inflammatory diseases such as nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cardiomyopathy, obesity, diabetes, neurodegenerative diseases, aging, and kidney injury, many of which are independent of type I IFNs 2,3,9 . It is tempting to suggest that STING activation in CD4 T cells leads to CD4 T-regs depletion that break tissue tolerance and exacerbates tissue inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…STING drives cytosolic DNA-induced type I IFNs production 1 . Recent research revealed that STING promotes inflammation in a variety of inflammatory diseases including nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, kidney injury, neurodegenerative diseases, cardiovascular diseases, obesity, diabetes, and aging 2–9 . The type I IFNs-independent function of STING has also emerged 10,11 .…”

Section: Introductionmentioning

confidence: 99%

“…How STING drives inflammation in vivo, independent of type I IFNs, remains unknown. The activation of NFκB or NLRP3 inflammasome by STING has been proposed 9,20 .…”

Section: Introductionmentioning

confidence: 99%

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The commonTMEM173 HAQ, AQalleles rescue CD4 T cellpenia, restore T-regs, and preventSAVI (N153S)inflammatory disease in mice

Aybar-Torres,

Saldarriaga,

Pham

et al. 2023

Preprint

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STING activation induces lymphocyte cell death that is independent of type I IFNs. Thein vivosignificance and mechanism of STING-mediated cell death is unclear. Using STING knock-in mice, we found that lymphocytes from theHAQ,AQ, andQ293mice are resistant to STING-mediated cell deathex vivo, establishing a critical role of STING residue 293 in cell death. CD4 T cellpenia is evident in STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING mutations. TheHAQ/SAVI(N153S)andAQ/SAVI(N153S)mice have similar spleen CD4 T cells as theWTmice reversing the CD4 T cellpenia by the gain-of-function N153S STING. TheHAQ/SAVI(N153S), AQ/SAVI(N153S)mice have more (∼10-fold, ∼20-fold, respectively) T-regs thanWT/SAVI(N153S)mice. Remarkably, while have comparable TBK1, IRF3, NFκB activation as theWT/SAVI, theAQ/SAVImice have no tissue inflammation, regular body weight, and normal lifespan. The type I IFNs-independent function of STING in health and diseases has been increasingly recognized. We propose that STING activation promotes tissue inflammation by depleting T-regs cellsin vivo. Billions of modern humans have the dominantHAQ, AQalleles. STING research and STING-targeting immunotherapy should considerTMEM173heterogeneity in humans.One-sentence summaryThe CommonTMEM173allelesHAQ, AQprevent SAVI disease.

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