Suppression of systemic autoimmunity by the innate immune adaptor STING
Authors
Sharma, ShrutieCampbell, Allison M.
Chan, Jennie
Schattgen, Stefan A.
Orlowski, Gregory M.
Nayar, Ribhu
Huyler, Annie H.
Nundel, Kerstin
Mohan, Chandra
Berg, Leslie J.
Shlomchik, Mark J.
Marshak-Rothstein, Ann
Fitzgerald, Katherine A.
Student Authors
Jennie ChanUMass Chan Affiliations
Department of PathologyDivision of Infectious Diseases and Immunology, Department of Medicine
Division of Rheumatology, Department of Medicine
Program in Innate Immunity
Document Type
Journal ArticlePublication Date
2015-02-17Keywords
IRF3STING
TLRs
autoimmunity
lupus
Immune System Diseases
Immunity
Skin and Connective Tissue Diseases
Metadata
Show full item recordAbstract
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.Source
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
DOI
10.1073/pnas.1420217112Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33487PubMed ID
25646421Related Resources
Rights
Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.ae974a485f413a2113503eed53cd6c53
10.1073/pnas.1420217112