Suppression of systemic autoimmunity by the innate immune adaptor STING
| Autor: | Mark J. Shlomchik, Katherine A. Fitzgerald, Jennie Chan, Ann Marshak-Rothstein, Shrutie Sharma, Leslie J. Berg, Ribhu Nayar, Allison M. Campbell, Kerstin Nündel, Annie H. Huyler, Stefan A. Schattgen, Chandra Mohan, Gregory M. Orlowski |
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| Rok vydání: | 2015 |
| Předmět: |
Autoimmunity
Inflammation Biology Lymphocyte Activation Systemic inflammation Proinflammatory cytokine Mice medicine Animals skin and connective tissue diseases Autoantibodies Multidisciplinary Innate immune system Autoantibody Membrane Proteins Dendritic Cells eye diseases Sting Gene Expression Regulation PNAS Plus Stimulator of interferon genes Immunology Interferon Regulatory Factor-3 Interferons medicine.symptom IRF3 |
| Zdroj: | Proceedings of the National Academy of Sciences. 112 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1420217112 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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