title: TLR7-dependent and FcgammaR-independent production of type I interferon in experimental mouse lupus.
abstract: Increased type I interferon (IFN-I) production and IFN-stimulated gene (ISG) expression are linked to the pathogenesis of systemic lupus erythematosus (SLE). Although the mechanisms responsible for dysregulated IFN-I production in SLE remain unclear, autoantibody-mediated uptake of endogenous nucleic acids is thought to play a role. 2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane) induces a lupus-like disease in mice characterized by immune complex nephritis with autoantibodies to DNA and ribonucleoproteins. We recently reported that TMPD also causes increased ISG expression and that the development of the lupus is completely dependent on IFN-I signaling (Nacionales, D.C., K.M. Kelly-Scumpia, P.Y. Lee, J.S. Weinstein, R. Lyons, E. Sobel, M. Satoh, and W.H. Reeves. 2007. Arthritis Rheum. 56:3770-3783). We show that TMPD elicits IFN-I production, monocyte recruitment, and autoantibody production exclusively through a Toll-like receptor (TLR) 7- and myeloid differentiation factor 88 (MyD88)-dependent pathway. In vitro studies revealed that TMPD augments the effect of TLR7 ligands but does not directly activate TLR7 itself. The effects of TMPD were amplified by the Y-linked autoimmune acceleration cluster, which carries a duplication of the TLR7 gene. In contrast, deficiency of Fcgamma receptors (FcgammaRs) did not affect the production of IFN-I. Collectively, the data demonstrate that TMPD-stimulated IFN-I production requires TLR7/MyD88 signaling and is independent of autoantibody-mediated uptake of ribonucleoproteins by FcgammaRs.
authors.affiliation: Division of Rheumatology and Clinical Immunology and Center for Autoimmune Disease, University of Florida, Gainesville, FL 32610, USA. puilee05@ufl.edu
authors.forename: Pui Y
authors.initials: PY
authors.lastname: Lee
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeuchi
authors.forename: Hideo
authors.initials: H
authors.lastname: Yoshida
authors.forename: Jason
authors.initials: J
authors.lastname: Weinstein
authors.forename: Erinn S
authors.initials: ES
authors.lastname: Kellner
authors.forename: Dina
authors.initials: D
authors.lastname: Nacionales
authors.forename: Tolga
authors.initials: T
authors.lastname: Barker
authors.forename: Kindra
authors.initials: K
authors.lastname: Kelly-Scumpia
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Himanshu
authors.initials: H
authors.lastname: Kumar
authors.forename: Taro
authors.initials: T
authors.lastname: Kawai
authors.forename: Minoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Westley H
authors.initials: WH
authors.lastname: Reeves
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D002460:Cell Line; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000276:immunology; D007370:Interferon Type I / Q000378:metabolism*; D015850:Interleukin-6 / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology*; D012261:Ribonucleoproteins / Q000378:metabolism; D013729:Terpenes / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D007166:Immunosuppressive Agents; D007370:Interferon Type I; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017452:Receptors, IgG; D012261:Ribonucleoproteins; D013729:Terpenes; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; C009042:pristane