Program in Innate Immunity; Division of Rheumatology, Department of Medicine; Division of Infectious Diseases and Immunology, Department of Medicine; Department of Pathology
Immune System Diseases | Immunity | Skin and Connective Tissue Diseases
Cytosolic DNA-sensing pathways that signal via Stimulator of interferon genes (STING) mediate immunity to pathogens and also promote autoimmune pathology in DNaseII- and DNaseIII-deficient mice. In contrast, we report here that STING potently suppresses inflammation in a model of systemic lupus erythematosus (SLE). Lymphoid hypertrophy, autoantibody production, serum cytokine levels, and other indicators of immune activation were markedly increased in STING-deficient autoimmune-prone mice compared with STING-sufficient littermates. As a result, STING-deficient autoimmune-prone mice had significantly shorter lifespans than controls. Importantly, Toll-like receptor (TLR)-dependent systemic inflammation during 2,6,10,14-tetramethylpentadecane (TMPD)-mediated peritonitis was similarly aggravated in STING-deficient mice. Mechanistically, STING-deficient macrophages failed to express negative regulators of immune activation and thus were hyperresponsive to TLR ligands, producing abnormally high levels of proinflammatory cytokines. This hyperreactivity corresponds to dramatically elevated numbers of inflammatory macrophages and granulocytes in vivo. Collectively these findings reveal an unexpected negative regulatory role for STING, having important implications for STING-directed therapies.
IRF3, STING, TLRs, autoimmunity, lupus
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DOI of Published Version
Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):E710-7. doi: 10.1073/pnas.1420217112. Epub 2015 Feb 2. Link to article on publisher's site
Proceedings of the National Academy of Sciences of the United States of America
Sharma S, Campbell AM, Chan J, Schattgen SA, Orlowski GM, Nayar R, Huyler AH, Nundel K, Mohan C, Berg LJ, Shlomchik MJ, Marshak-Rothstein A, Fitzgerald KA. (2015). Suppression of systemic autoimmunity by the innate immune adaptor STING. Morningside Graduate School of Biomedical Sciences Student Publications. https://doi.org/10.1073/pnas.1420217112. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/2012