title: The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity.
abstract: The molecules and pathways that fine-tune innate inflammatory responses mediated by Toll-like receptor 7 (TLR7) remain to be fully elucidated. Using an unbiased genome-scale screen with short hairpin RNA (shRNA), we identified the receptor TREML4 as an essential positive regulator of TLR7 signaling. Macrophages from Treml4(-/-) mice were hyporesponsive to TLR7 agonists and failed to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MyD88 to TLR7. TREML4 deficiency reduced the production of inflammatory cytokines and autoantibodies in MRL/lpr mice, which are prone to systemic lupus erythematosus (SLE), and inhibited the antiviral immune response to influenza virus. Our data identify TREML4 as a positive regulator of TLR7 signaling and provide insight into the molecular mechanisms that control antiviral immunity and the development of autoimmunity.
authors.affiliation: Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Zaida G
authors.initials: ZG
authors.lastname: Ramirez-Ortiz
authors.affiliation: Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Prasad
authors.affiliation: Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Griffith
authors.affiliation: University of North Carolina Kidney Center, Burnett Womack Building, Chapel Hill, North Carolina, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Pendergraft
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Tai
authors.affiliation: Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.affiliation: 1] Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. [2] Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: El Khoury
authors.affiliation: 1] Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Hacohen
authors.affiliation: Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
authors.forename: Terry K
authors.initials: TK
authors.lastname: Means
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008264:Macrophages / Q000502:physiology* / Q000821:virology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009975:Orthomyxoviridae / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D018836:Inflammation Mediators; D007370:Interferon Type I; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; D050794:STAT1 Transcription Factor; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C539378:Treml4 protein, mouse; D048051:p38 Mitogen-Activated Protein Kinases
references.citation: Curr Opin Immunol. 2013 Dec;25(6):720-7
references.pmid: 24246388
references.citation: Nat Immunol. 2013 Sep;14(9):917-26
references.pmid: 23892722
references.citation: Sci Transl Med. 2014 Jul 2;6(243):243ra86
references.pmid: 24990881
references.citation: Am J Hum Genet. 2014 Jul 3;95(1):66-76
references.pmid: 24975946
references.citation: Nat Genet. 2000 Jul;25(3):357-61
references.pmid: 10888890
references.citation: Sci Rep. 2014;4:3792
references.pmid: 24445780
references.citation: Immunol Cell Biol. 2014 Oct;92(9):761-9
references.pmid: 25027037
references.citation: Nature. 2001 Apr 26;410(6832):1103-7
references.pmid: 11323674
references.citation: Am J Hum Genet. 2002 Sep;71(3):656-62
references.pmid: 12080485
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 1;99(20):12859-64
references.pmid: 12232043
references.citation: Science. 2004 Mar 5;303(5663):1529-31
references.pmid: 14976261
references.citation: Arthritis Rheum. 2004 Jun;50(6):1861-72
references.pmid: 15188363
references.citation: Nat Rev Immunol. 2004 Jul;4(7):499-511
references.pmid: 15229469
references.citation: Nature. 1991 May 30;351(6325):355-6
references.pmid: 1851964
references.citation: J Exp Med. 2004 Dec 6;200(11):1419-26
references.pmid: 15557347
references.citation: Nat Immunol. 2005 Jun;6(6):579-86
references.pmid: 15895090
references.citation: J Exp Med. 2005 Jul 18;202(2):321-31
references.pmid: 16027240
references.citation: Cell. 2006 Mar 24;124(6):1283-98
references.pmid: 16564017
references.citation: Science. 2006 Jun 16;312(5780):1669-72
references.pmid: 16709748
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9970-5
references.pmid: 16777955
references.citation: J Immunol. 2006 Aug 15;177(4):2051-5
references.pmid: 16887962
references.citation: J Immunol. 2006 Sep 15;177(6):3520-4
references.pmid: 16951310
references.citation: Immunity. 2006 Sep;25(3):429-40
references.pmid: 16973388
references.citation: Immunity. 2006 Sep;25(3):417-28
references.pmid: 16973389
references.citation: Nat Immunol. 2006 Dec;7(12):1266-73
references.pmid: 17110943
references.citation: Immunity. 2007 Nov;27(5):801-10
references.pmid: 17997333
references.citation: Eur J Immunol. 2007 Dec;37(12):3582-6
references.pmid: 18034431
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Dec;293(6):L1377-84
references.pmid: 17905855
references.citation: J Clin Invest. 2008 Apr;118(4):1417-26
references.pmid: 18340381
references.citation: Immunity. 2008 Aug 15;29(2):249-60
references.pmid: 18691914
references.citation: Brain. 2008 Nov;131(Pt 11):3081-91
references.pmid: 18790823
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20380-5
references.pmid: 19091943
references.citation: J Immunol. 2009 Feb 1;182(3):1278-86
references.pmid: 19155473
references.citation: J Cell Biol. 2009 Jan 26;184(2):215-23
references.pmid: 19171755
references.citation: Nat Immunol. 2009 Apr;10(4):340-7
references.pmid: 19295630
references.citation: Curr Opin Immunol. 2009 Feb;21(1):38-46
references.pmid: 19230638
references.citation: J Clin Invest. 2009 Jun;119(6):1489-501
references.pmid: 19436112
references.citation: J Immunol. 2010 Feb 15;184(4):1840-8
references.pmid: 20089701
references.citation: Annu Rev Immunol. 2011;29:185-214
references.pmid: 21219183
references.citation: J Immunol. 2012 Feb 1;188(3):1147-55
references.pmid: 22210914
references.citation: N Engl J Med. 2013 Jan 10;368(2):107-16
references.pmid: 23150908
references.citation: N Engl J Med. 2013 Jan 10;368(2):117-27
references.pmid: 23150934
references.citation: Hum Immunol. 2013 Jun;74(6):730-7
references.pmid: 23459077
references.citation: Clin Chim Acta. 2013 Jun 5;421:184-90
references.pmid: 23535507
references.citation: Nat Rev Immunol. 2013 Jun;13(6):453-60
references.pmid: 23681101