title: Suppression of systemic autoimmunity by the innate immune adaptor STING.
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.
authors: Program in Innate Immunity, Division of Infectious Diseases.
authors: Shruti
authors: S
authors: Sharma
authors: Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06519;
authors: Allison M
authors: AM
authors: Campbell
authors: Program in Innate Immunity, Division of Infectious Diseases.
authors: Jennie
authors: J
authors: Chan
authors: Program in Innate Immunity, Division of Infectious Diseases.
authors: Stefan A
authors: SA
authors: Schattgen
authors: Department of Pathology, and.
authors: Gregory M
authors: GM
authors: Orlowski
authors: Department of Pathology, and.
authors: Ribhu
authors: R
authors: Nayar
authors: Program in Innate Immunity, Division of Infectious Diseases.
authors: Annie H
authors: AH
authors: Huyler
authors: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605;
authors: Kerstin
authors: K
authors: Nündel
authors: Department of Immunology and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors: Chandra
authors: C
authors: Mohan
authors: Department of Pathology, and.
authors: Leslie J
authors: LJ
authors: Berg
authors: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261; and.
authors: Mark J
authors: MJ
authors: Shlomchik
authors: Division of Rheumatology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605; ann.rothstein@umassmed.edu kate.fitzgerald@umassmed.edu.
authors: Ann
authors: A
authors: Marshak-Rothstein
authors: Program in Innate Immunity, Division of Infectious Diseases, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7489 Trondheim, Norway ann.rothstein@umassmed.edu kate.fitzgerald@umassmed.edu.
authors: Katherine A
authors: KA
authors: Fitzgerald
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology; D005786:Gene Expression Regulation / Q000502:physiology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000502:physiology; D007372:Interferons / Q000502:physiology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D000099197:STING Protein
chemical_list: D001323:Autoantibodies; D050838:Interferon Regulatory Factor-3; D007372:Interferons; D008565:Membrane Proteins; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein
keywords: IRF3; STING; TLRs; autoimmunity; lupus
references: Immunity. 2006 Sep;25(3):417-28
references: 16973389
references: Immunity. 2006 Sep;25(3):383-92
references: 16979570
references: Nat Rev Immunol. 2006 Nov;6(11):823-35
references: 17063184
references: Nature. 2006 Oct 26;443(7114):998-1002
references: 17066036
references: Curr Opin Immunol. 2006 Dec;18(6):676-82
references: 17011763
references: Nat Genet. 2007 Sep;39(9):1065-7
references: 17660818
references: Annu Rev Immunol. 2008;26:535-84
references: 18303999
references: Immunobiology. 2008;213(3-4):225-35
references: 18406369
references: Arthritis Rheum. 2008 Apr;58(4):1107-15
references: 18383384
references: Arthritis Rheum. 2008 Aug;58(8):2481-7
references: 18668568
references: Cell. 2008 Aug 22;134(4):587-98
references: 18724932
references: Nature. 2008 Oct 2;455(7213):674-8
references: 18724357
references: J Exp Med. 2008 Dec 22;205(13):2995-3006
references: 19047436
references: J Biol Chem. 2009 Mar 27;284(13):8217-21
references: 19008218
references: Trends Immunol. 2009 Sep;30(9):455-64
references: 19699150
references: Nature. 2009 Oct 8;461(7265):788-92
references: 19776740
references: Lupus. 2010 Sep;19(10):1219-28
references: 20530519
references: Nat Immunol. 2010 Nov;11(11):997-1004
references: 20890285
references: Arthritis Rheum. 2011 Mar;63(3):738-48
references: 21305501
references: J Immunol. 2011 Mar 15;186(6):3283-8
references: 21368237
references: Sci Transl Med. 2011 Mar 9;3(73):73ps9
references: 21389262
references: Semin Immunol. 2011 Apr;23(2):106-12
references: 21306913
references: Immunity. 2011 Apr 22;34(4):590-601
references: 21458307
references: Genes Immun. 2011 Jun;12(4):263-9
references: 21248775
references: Immunity. 2011 Aug 26;35(2):194-207
references: 21820332
references: Nat Rev Immunol. 2011 Nov;11(11):762-74
references: 21984070
references: J Exp Med. 2012 Jan 16;209(1):139-55
references: 22231304
references: Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3909-14
references: 22355111
references: Clin Exp Immunol. 2012 May;168(2):178-85
references: 22471278
references: J Clin Invest. 2012 Oct;122(10):3464-6
references: 23154274
references: Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19386-91
references: 23132945
references: Nat Immunol. 2013 Jan;14(1):19-26
references: 23238760
references: Science. 2013 Feb 15;339(6121):786-91
references: 23258413
references: Trends Immunol. 2013 Mar;34(3):137-43
references: 23103127
references: J Immunol. 2013 Sep 1;191(5):2104-14
references: 23918976
references: J Immunol. 2013 Oct 1;191(7):3509-13
references: 23986532
references: J Immunol. 2014 Jun 15;192(12):5571-8
references: 24799564
references: N Engl J Med. 2014 Aug 7;371(6):507-18
references: 25029335
references: J Clin Invest. 2014 Dec;124(12):5516-20
references: 25401470
references: Oncogene. 2000 May 15;19(21):2532-47
references: 10851052
references: Immunity. 2000 Oct;13(4):539-48
references: 11070172
references: J Immunol. 2003 May 1;170(9):4818-25
references: 12707364
references: J Hum Genet. 2005;50(3):107-11
references: 15723160
references: J Exp Med. 2005 Jul 18;202(2):321-31
references: 16027240
references: Eur J Immunol. 2006 May;36(5):1296-308
references: 16541466
references: Nat Genet. 2006 Aug;38(8):917-20
references: 16845398
references: Cell Immunol. 2006 Mar;240(1):5-13
references: 16854402