title: RNA sensing by conventional dendritic cells is central to the development of lupus nephritis.
abstract: Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified. In this investigation we have shown that conventional DC expression of TLR7 is essential for severe autoimmunity in the Sle1Tg7 model of SLE. We show that a novel expanding CD11b(+) conventional DC subpopulation dominates the infiltrating renal inflammatory milieu, localizing to the glomeruli. Moreover, exposure of human myeloid DCs to IFN-α or Flu increases TLR7 expression, suggesting they may have a role in self-RNA recognition pathways in clinical disease. To our knowledge, this study is the first to highlight the importance of conventional DC-TLR7 expression for kidney pathogenesis in a murine model of SLE.
authors.affiliation: Singapore Immunology Network, A*STAR, 138648 Singapore;
authors.forename: Teja
authors.initials: T
authors.lastname: Celhar
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, 138673 Singapore;
authors.forename: Richard
authors.initials: R
authors.lastname: Hopkins
authors.affiliation: Singapore Immunology Network, A*STAR, 138648 Singapore;
authors.forename: Susannah I
authors.initials: SI
authors.lastname: Thornhill
authors.affiliation: Singapore Immunology Network, A*STAR, 138648 Singapore;
authors.forename: Raquel
authors.initials: R
authors.lastname: De Magalhaes
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093;
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Hwang
authors.affiliation: Singapore Immunology Network, A*STAR, 138648 Singapore;
authors.forename: Hui-Yin
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Singapore Immunology Network, A*STAR, 138648 Singapore; School of Biological Sciences, Nanyang Technological University, 637551 Singapore;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yasuga
authors.affiliation: Singapore Immunology Network, A*STAR, 138648 Singapore; Institute of Molecular and Cell Biology, A*STAR, 138673 Singapore;
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Jones
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093;
authors.forename: Jose
authors.initials: J
authors.lastname: Casco
authors.affiliation: Singapore Immunology Network, A*STAR, 138648 Singapore;
authors.forename: Bernett
authors.initials: B
authors.lastname: Lee
authors.affiliation: Department of Pathology, National University Hospital, 119074 Singapore;
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Thamboo
authors.affiliation: Department of Pathology, Baylor University Medical Center, Dallas, TX 75246;
authors.forename: Xin J
authors.initials: XJ
authors.lastname: Zhou
authors.affiliation: Singapore Immunology Network, A*STAR, 138648 Singapore;
authors.forename: Michael
authors.initials: M
authors.lastname: Poidinger
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, 138673 Singapore; Institute of Biomedical Studies, Baylor University, Waco, TX76798.
authors.forename: John E
authors.initials: JE
authors.lastname: Connolly
authors.affiliation: Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093;
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.affiliation: Singapore Immunology Network, A*STAR, 138648 Singapore; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9093; School of Biological Sciences, Nanyang Technological University, 637551 Singapore; annamarie_fairhurst@immunol.a-star.edu.sg.
authors.forename: Anna-Marie
authors.initials: AM
authors.lastname: Fairhurst
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D039481:CD11b Antigen / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000378:metabolism*; D005434:Flow Cytometry; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007678:Kidney Glomerulus / Q000166:cytology / Q000473:pathology; D008181:Lupus Nephritis / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D018709:Statistics, Nonparametric; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D039481:CD11b Antigen; D017931:DNA Primers; C509295:ITGAM protein, human; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7
keywords: SLE; TLR7; autoimmunity; dendritic cells; nephritis