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Innate IL-17A–Producing Leukocytes Promote Acute Kidney Injury via Inflammasome and Toll-Like Receptor Activation
- Source :
- The American Journal of Pathology. (5):1411-1418
- Publisher :
- American Society for Investigative Pathology. Published by Elsevier Inc.
-
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.
- Subjects :
- CD4-Positive T-Lymphocytes
Male
Inflammasomes
Inflammation
Biology
Kidney
Antibodies
Nephrotoxicity
Pathology and Forensic Medicine
medicine
Leukocytes
Animals
RNA, Messenger
Toll-like receptor
Interleukin-17
Acute kidney injury
Kidney metabolism
Inflammasome
Acute Kidney Injury
Nuclear Receptor Subfamily 1, Group F, Member 3
medicine.disease
Toll-Like Receptor 2
CARD Signaling Adaptor Proteins
Killer Cells, Natural
Mice, Inbred C57BL
TLR2
Gene Expression Regulation
Neutrophil Infiltration
Immunology
medicine.symptom
Chemokines
Cisplatin
Apoptosis Regulatory Proteins
Inflammasome complex
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 00029440
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- The American Journal of Pathology
- Accession number :
- edsair.doi.dedup.....787671b03fee582302616ed8341c3570
- Full Text :
- https://doi.org/10.1016/j.ajpath.2014.01.023