title: Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice.
abstract: How bacterial or viral infections trigger flares of autoimmunity is poorly understood. As toll-like receptor (TLR)-9 activation by exogenous or endogenous CpG-DNA may contribute to disease activity of systemic lupus erythematosus, we examined the effects of CpG-oligodeoxynucleotides (ODN) or DNA derived from Escherichia coli (E. coli) on the course of nephritis in MRL(lpr/lpr) mice. In kidneys of these mice, TLR9 localized to glomerular, tubulointerstitial, and perivascular infiltrates. After intraperitoneal injection labeled CpG-ODN localized to glomerular and interstitial macrophages and dendritic cells in nephritic kidneys of MRL(lpr/lpr) mice but not in healthy MRL controls. Furthermore, murine J774 macrophages and splenocytes from MRL(lpr/lpr) mice, but not tubular epithelial cells, renal fibroblasts, or mesangial cells, expressed TLR9 and up-regulated CCL5/RANTES mRNA upon stimulation with CpG-ODN in vitro. In vivo both E. coli DNA and CpG-ODN increased serum DNA autoantibodies of the IgG2a isotype in MRL(lpr/lpr) mice. This was associated with progression of mild to crescentic glomerulonephritis, interstitial fibrosis, and heavy proteinuria. CpG-ODN increased renal CCL2/MCP-1 and CCL5/RANTES expression associated with increased glomerular and interstitial leukocyte recruitment. In contrast control GpC-ODN had no effect. We conclude that TLR9 activation triggers disease activity of systemic autoimmunity, for example, lupus nephritis, and that adaptive and innate immune mechanisms contribute to the CpG-DNA-induced progression of lupus nephritis.
authors.affiliation: Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University Munich, Germany. hjanders@med.uni-muenchen.de
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
authors.forename: Volker
authors.initials: V
authors.lastname: Vielhauer
authors.forename: Vaclav
authors.initials: V
authors.lastname: Eis
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Linde
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Guillermo
authors.initials: G
authors.lastname: Perez de Lema
authors.forename: Frank
authors.initials: F
authors.lastname: Strutz
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
authors.forename: Mark
authors.initials: M
authors.lastname: Rutz
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000097:blood; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D004247:DNA / Q000276:immunology*; D004269:DNA, Bacterial / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000502:physiology*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004926:Escherichia coli / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000097:blood; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008181:Lupus Nephritis / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*; D051217:Toll-Like Receptor 9
chemical_list: D000974:Antibodies, Antinuclear; C408982:CPG-oligonucleotide; D018925:Chemokines; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D009838:Oligodeoxyribonucleotides; D019713:Receptors, CCR5; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D004247:DNA