title: An essential role of interleukin-17 receptor signaling in the development of autoimmune glomerulonephritis.
abstract: In recent years, proinflammatory cytokines in the nephritic kidney appear to contribute to the pathogenesis of AGN. The complex inflammatory cytokine network that drives renal pathology is poorly understood. IL-17, the signature cytokine of Th17 cells, which promotes autoimmune pathology in a variety of settings, is beginning to be identified in acute and chronic kidney diseases as well. However, the role of IL-17-mediated renal damage in the nephritic kidney has not been elucidated. Here, with the use of a murine model of experimental AGN, we showed that IL-17RA signaling is critical for the development of renal pathology. Despite normal systemic autoantibody response and glomerular immune-complex deposition, IL-17RA(-/-) mice exhibit a diminished influx of inflammatory cells and kidney-specific expression of IL-17 target genes correlating with disease resistance in AGN. IL-17 enhanced the production of proinflammatory cytokines and chemokines from tECs. Finally, we were able to show that neutralization of IL-17A ameliorated renal pathology in WT mice following AGN. These results clearly demonstrated that IL-17RA signaling significantly contributes to renal tissue injury in experimental AGN and suggest that blocking IL-17RA may be a promising therapeutic strategy for the treatment of proliferative and crescentic glomerulonephritis.
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pennsylvania, USA; and.
authors.forename: Kritika
authors.initials: K
authors.lastname: Ramani
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pennsylvania, USA; and.
authors.forename: Sudesh
authors.initials: S
authors.lastname: Pawaria
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pennsylvania, USA; and.
authors.forename: Kelly
authors.initials: K
authors.lastname: Maers
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pennsylvania, USA; and Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Huppler
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pennsylvania, USA; and.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
authors.affiliation: Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pennsylvania, USA; and psb13@pitt.edu.
authors.forename: Partha S
authors.initials: PS
authors.lastname: Biswas
mesh_terms: D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004357:Drug Synergism; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D020381:Interleukin-17 / Q000494:pharmacology; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D053722:Receptors, Interleukin-17 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016207:Cytokines; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D012333:RNA, Messenger; D053722:Receptors, Interleukin-17; D014409:Tumor Necrosis Factor-alpha
keywords: IL-17; inflammation; kidney