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dc.contributor.authorSharma, Shrutie
dc.contributor.authorCampbell, Allison M.
dc.contributor.authorChan, Jennie
dc.contributor.authorSchattgen, Stefan A.
dc.contributor.authorOrlowski, Gregory M.
dc.contributor.authorNayar, Ribhu
dc.contributor.authorHuyler, Annie H.
dc.contributor.authorNundel, Kerstin
dc.contributor.authorMohan, Chandra
dc.contributor.authorBerg, Leslie J.
dc.contributor.authorShlomchik, Mark J.
dc.contributor.authorMarshak-Rothstein, Ann
dc.contributor.authorFitzgerald, Katherine A.
dc.date2022-08-11T08:08:56.000
dc.date.accessioned2022-08-23T16:12:52Z
dc.date.available2022-08-23T16:12:52Z
dc.date.issued2015-02-17
dc.date.submitted2017-09-06
dc.identifier.citation<p>Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):E710-7. doi: 10.1073/pnas.1420217112. Epub 2015 Feb 2. <a href="https://doi.org/10.1073/pnas.1420217112">Link to article on publisher's site</a></p>
dc.identifier.issn0027-8424 (Linking)
dc.identifier.doi10.1073/pnas.1420217112
dc.identifier.pmid25646421
dc.identifier.urihttp://hdl.handle.net/20.500.14038/33487
dc.description.abstractCytosolic 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.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=25646421&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsPublisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.
dc.subjectIRF3
dc.subjectSTING
dc.subjectTLRs
dc.subjectautoimmunity
dc.subjectlupus
dc.subjectImmune System Diseases
dc.subjectImmunity
dc.subjectSkin and Connective Tissue Diseases
dc.titleSuppression of systemic autoimmunity by the innate immune adaptor STING
dc.typeJournal Article
dc.source.journaltitleProceedings of the National Academy of Sciences of the United States of America
dc.source.volume112
dc.source.issue7
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3035&amp;context=gsbs_sp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_sp/2012
dc.identifier.contextkey10714507
refterms.dateFOA2022-08-23T16:12:52Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathgsbs_sp/2012
dc.contributor.departmentDepartment of Pathology
dc.contributor.departmentDivision of Infectious Diseases and Immunology, Department of Medicine
dc.contributor.departmentDivision of Rheumatology, Department of Medicine
dc.contributor.departmentProgram in Innate Immunity
dc.source.pagesE710-7
dc.contributor.studentJennie Chan


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