title: Innate IL-17A-producing leukocytes promote acute kidney injury via inflammasome and Toll-like receptor activation.
abstract: In acute kidney injury, which is a significant cause of morbidity and mortality, cytokines and leukocytes promote inflammation and injury. We examined the pathogenic role of IL-17A in cisplatin-induced acute kidney injury. Intrarenal IL-17A mRNA transcription and protein expression were increased in wild-type mice after cisplatin-induced renal injury. An important role for IL-17A in the nephrotoxicity of cisplatin was demonstrated by observing protection from cisplatin-induced functional and histological renal injury in Il17a(-/-) and Rorγt(-/-) mice, as well as in mice treated pre-emptively with anti-IL-17A antibodies. Both renal injury and renal IL-1β and IL-17A production were attenuated in Asc(-/-) and Tlr2(-/-) mice, suggesting that cisplatin induces endogenous TLR2 ligand production and activates the ASC-dependent inflammasome complex, resulting in IL-1β and injurious IL-17A production. Neutrophils and natural killer cells are the likely targets of these pathways, because combined depletion of these cells was strongly protective; anti-IL-17A antibodies had no additional effect in this setting. Although IL-17A can also be produced by CD4(+) and γδ T cells, IL-17A from those cells does not contribute to renal injury. Cisplatin-induced injury was unchanged in γδ T-cell-deficient mice, whereas Il17a(-/-) CD4(+) T cells induced similar injury as did wild-type CD4(+) T cells on transfer to cisplatin-injected Rag1(-/-) mice. These studies demonstrate an important role for TLR2, the ASC inflammasome, and IL-17A in innate leukocytes in cisplatin-induced renal injury.
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Victoria, Australia.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Chan
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Victoria, Australia.
authors.forename: Maliha A
authors.initials: MA
authors.lastname: Alikhan
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Victoria, Australia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Odobasic
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Victoria, Australia.
authors.forename: Poh Y
authors.initials: PY
authors.lastname: Gan
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Victoria, Australia.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Khouri
authors.affiliation: Department of Internal Medicine III and Clinics, Hamburg-Eppendorf University Clinic, Hamburg, Germany.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Steinmetz
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Victoria, Australia.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Mansell
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Victoria, Australia; Department of Nephrology, Monash Health, Victoria, Australia.
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Victoria, Australia; Department of Nephrology, Monash Health, Victoria, Australia. Electronic address: stephen.holdsworth@monash.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Victoria, Australia; Department of Nephrology, Monash Health, Victoria, Australia.
authors.forename: Shaun A
authors.initials: SA
authors.lastname: Summers
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism*; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D018925:Chemokines; D058847:Inflammasomes; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C498534:Pycard protein, mouse; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D002945:Cisplatin