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Article
Suppression of systemic autoimmunity by the innate immune adaptor STING
GSBS Student Publications
  • Shrutie Sharma, University of Massachusetts Medical School
  • Allison M. Campbell, Yale University
  • Jennie Chan, University of Massachusetts Medical School
  • Stefan A. Schattgen, University of Massachusetts Medical School
  • Gregory M. Orlowski, University of Massachusetts Medical School
  • Ribhu Nayar, University of Massachusetts Medical School
  • Annie H. Huyler, University of Massachusetts Medical School
  • Kerstin Nundel, University of Massachusetts Medical School
  • Chandra Mohan, University of Texas Southwestern Medical Center at Dallas
  • Leslie J. Berg, University of Pittsburgh
  • Mark J. Shlomchik, Yale University School of Medicine
  • Ann Marshak-Rothstein, University of Massachusetts Medical School
  • Katherine A. Fitzgerald, University of Massachusetts Medical School
Student Author(s)
Jennie Chan
GSBS Program
Immunology & Microbiology
Publication Date
2015-2-17
UMMS Affiliation
Program in Innate Immunity; Division of Rheumatology, Department of Medicine; Division of Infectious Diseases and Immunology, Department of Medicine; Department of Pathology
Document Type
Article
Abstract

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.

Keywords
  • IRF3,
  • STING,
  • TLRs,
  • autoimmunity,
  • lupus
Rights and Permissions
Publisher PDF posted as allowed by the publisher's author rights policy at http://www.pnas.org/site/aboutpnas/authorfaq.xhtml.
DOI of Published Version
10.1073/pnas.1420217112
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

Related Resources

Link to Article in PubMed

PubMed ID
25646421
Citation Information
Shrutie Sharma, Allison M. Campbell, Jennie Chan, Stefan A. Schattgen, et al.. "Suppression of systemic autoimmunity by the innate immune adaptor STING" Vol. 112 Iss. 7 (2015) ISSN: 0027-8424 (Linking)
Available at: http://works.bepress.com/katherine_fitzgerald/209/