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 progress, 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 initial activation and the triggering of cytokine production responsible for inflammatory disease.
The second aim i s to study the mechanisms by which Trex1 may negatively 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.
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| Barral, Paola M; Sarkar, Devanand; Su, Zao-zhong et al. (2009) Functions of the cytoplasmic RNA sensors RIG-I and MDA-5: key regulators of innate immunity. Pharmacol Ther 124:219-34 |
| Ishikawa, Hiroki; Ma, Zhe; Barber, Glen N (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788-92 |
