Innate IL-17A-producing leukocytes promote acute kidney injury via inflammasome and Toll-like receptor activation

Am J Pathol. 2014 May;184(5):1411-8. doi: 10.1016/j.ajpath.2014.01.023. Epub 2014 Mar 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / pathology*
  • Animals
  • Antibodies / pharmacology
  • Apoptosis Regulatory Proteins / metabolism
  • CARD Signaling Adaptor Proteins
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Chemokines / genetics
  • Chemokines / metabolism
  • Cisplatin / adverse effects
  • Gene Expression Regulation / drug effects
  • Inflammasomes / drug effects
  • Inflammasomes / metabolism*
  • Interleukin-17 / biosynthesis*
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism
  • Kidney / metabolism
  • Kidney / pathology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Leukocytes / drug effects
  • Leukocytes / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Neutrophil Infiltration / drug effects
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Toll-Like Receptor 2 / metabolism*


  • Antibodies
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Chemokines
  • Inflammasomes
  • Interleukin-17
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Pycard protein, mouse
  • RNA, Messenger
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Cisplatin