title: Bacterial CpG-DNA aggravates immune complex glomerulonephritis: role of TLR9-mediated expression of chemokines and chemokine receptors.
abstract: Immune complex glomerulonephritis (GN) often deteriorates during infection with viruses and bacteria that, in contrast to mammals, have DNA that contains many unmethylated CpG motifs. Balb/c mice with horse apoferritin-induced GN (HAF-GN) were treated with either saline, CpG-oligodeoxynucleotides (ODN), or control GpC-ODN. Only CpG-ODN exacerbated HAF-GN with an increase of glomerular macrophages, which was associated with massive albuminuria and increased renal MCP-1/CCL2, RANTES/CCL5, CCR1, CCR2, and CCR5 mRNA expression. CpG-ODN induced a Th1 response as indicated by serum anti-HAF IgG(2a) titers, mesangial IgG(2a) deposits, and splenocyte IFN-gamma secretion. Messenger RNA for the CpG-DNA receptor Toll-like reeptor 9 (TLR9) was present in kidneys with HAF-GN but not in normal kidneys. The source of TLR9 mRNA in HAF-GN could be infiltrating macrophages or intrinsic renal cells, e.g., mesangial cells; but, in vitro, only murine J774 macrophages expressed TLR9. In J774 cells, CpG-ODN induced the chemokines MCP-1/CCL2 and RANTES/CCL5 and the chemokine receptors CCR1 and CCR5. It is concluded that CpG-DNA can aggravate preexisting GN via a shift toward a Th1 response but also by a novel pathway involving TLR9-mediated chemokine and chemokine receptor expression by macrophages, which may contribute to the enhanced glomerular macrophage recruitment and activation. This mechanism may be relevant during infection-triggered exacerbation of human immune-complex GN and other immune-mediated diseases in general.
authors.affiliation: Nephrological Center, Medical Policlinic, University of Munich, Munich, Germany.
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
authors.forename: Bernhard
authors.initials: B
authors.lastname: Banas
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Linde
authors.forename: Lars
authors.initials: L
authors.lastname: Weller
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Stefan
authors.initials: S
authors.lastname: Martin
authors.forename: Volker
authors.initials: V
authors.lastname: Vielhauer
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
mesh_terms: D000818:Animals; D000917:Antibody Formation; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D004269:DNA, Bacterial / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005921:Glomerulonephritis / Q000235:genetics* / Q000503:physiopathology*; D007105:Immune Complex Diseases / Q000235:genetics* / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D014018:Tissue Distribution; D051217:Toll-Like Receptor 9
chemical_list: C515300:CCR1 protein, human; C408982:CPG-oligonucleotide; C515301:Ccr1 protein, mouse; D018925:Chemokines; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9