Our data indicates that STING (Stimulator of interferon genes) controls a key cytosolic DNA-sensing pathway and is responsible for DNaseII-deficient lethality and chronic polyarthritis (CP) as well as TREX1-mediated SLE-like disease in mice. For example, DNaseII mice die during embryonic development due to undigested DNA derived from apoptotic cells activating DNA sensors that trigger the production of type I IFN and pro- inflammatory cytokines. DNaseII-/- mice are born normally in the absence of STING, however, without any signs of inflammation-aggravated disease. Further, TREX1-/- mice which have a median lifespan of 10 weeks due to the development of inflammatory myocarditis remain viable when crossed onto a STING-/- background, and do not exhibit such disease. Mutations inTREX1 have been shown to be involved in Aicardi-Goutieres syndrome (AGS) in humans, typified by high levels of circulating type I IFN and early death. Despite this significant progres, the mechanisms that control STING function and the cytosolic DNA signaling pathway remain to be fully clarified. We thus propose two aims. The first is to further understand the mechanisms controlling STING function, such as by phosphorylation and the triggering of cytokine production responsible for inflammatory disease.
The second aim i s to study the mechanisms by which Trex1 may regulate STING. These objectives will shed considerable insight into mechanisms of innate immunity as well as into the causes of inflammatory disease.
More than 20% of the population of the United States (US) has been reported to suffer from inflammatory disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Both of these syndromes have no known etiology and the mechanisms of disease initiation and progression remain unclear. We have found a potential cause of these diseases that could be targeted by therapeutics to prevent inflammatory-related disease.
|Araujo, Alan Moreira de; Antunes, Maísa Mota; Mattos, Matheus Silvério et al. (2018) Liver Immune Cells Release Type 1 Interferon Due to DNA Sensing and Amplify Liver Injury from Acetaminophen Overdose. Cells 7:|
|Konno, Hiroyasu; Yamauchi, Shota; Berglund, Anders et al. (2018) Suppression of STING signaling through epigenetic silencing and missense mutation impedes DNA damage mediated cytokine production. Oncogene 37:2037-2051|
|Konno, Hiroyasu; Chinn, Ivan K; Hong, Diana et al. (2018) Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING. Cell Rep 23:1112-1123|
|Costa Franco, Miriam M; Marim, Fernanda; Guimarães, Erika S et al. (2018) Brucella abortus Triggers a cGAS-Independent STING Pathway To Induce Host Protection That Involves Guanylate-Binding Proteins and Inflammasome Activation. J Immunol 200:607-622|
|Takahashi, Akiko; Loo, Tze Mun; Okada, Ryo et al. (2018) Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat Commun 9:1249|
|Ahn, Jeonghyun; Xia, Tianli; Rabasa Capote, Ailem et al. (2018) Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells. Cancer Cell 33:862-873.e5|
|Ahn, Jeonghyun; Son, Sehee; Oliveira, Sergio C et al. (2017) STING-Dependent Signaling Underlies IL-10 Controlled Inflammatory Colitis. Cell Rep 21:3873-3884|
|Dou, Zhixun; Ghosh, Kanad; Vizioli, Maria Grazia et al. (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:402-406|
|Swanson, Karen V; Junkins, Robert D; Kurkjian, Cathryn J et al. (2017) A noncanonical function of cGAMP in inflammasome priming and activation. J Exp Med 214:3611-3626|
|Ni, Guoxin; Konno, Hiroyasu; Barber, Glen N (2017) Ubiquitination of STING at lysine 224 controls IRF3 activation. Sci Immunol 2:|
Showing the most recent 10 out of 30 publications