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

Amy Chan, Maliha Alikhan, Dragana Odobasic, Poh Yi Gan, Mary Khouri, Oliver Steinmetz, Ashley Scott Mansell, Arthur Richard Kitching, Stephen Roger Holdsworth, Shaun Andrew Summers

Research output: Contribution to journalArticleResearchpeer-review

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 Rorgammat(-/-) mice, as well as in mice treated pre-emptively with anti-IL-17A antibodies. Both renal injury and renal IL-1beta 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-1beta 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 gammadelta T cells, IL-17A from those cells does not contribute to renal injury. Cisplatin-induced injury was unchanged in gammadelta 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.
Original languageEnglish
Pages (from-to)1411 - 1418
Number of pages8
JournalAmerican Journal of Pathology
Volume184
Issue number5
DOIs
Publication statusPublished - 2014

Cite this

@article{c359b790c79d46fb8deb9c54a2a53e50,
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 Rorgammat(-/-) mice, as well as in mice treated pre-emptively with anti-IL-17A antibodies. Both renal injury and renal IL-1beta 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-1beta 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 gammadelta T cells, IL-17A from those cells does not contribute to renal injury. Cisplatin-induced injury was unchanged in gammadelta 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.",
author = "Amy Chan and Maliha Alikhan and Dragana Odobasic and Gan, {Poh Yi} and Mary Khouri and Oliver Steinmetz and Mansell, {Ashley Scott} and Kitching, {Arthur Richard} and Holdsworth, {Stephen Roger} and Summers, {Shaun Andrew}",
year = "2014",
doi = "10.1016/j.ajpath.2014.01.023",
language = "English",
volume = "184",
pages = "1411 -- 1418",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "American Society for Investigative Pathology",
number = "5",

}

Innate IL-17A-producing leukocytes promote acute kidney injury via inflammasome and Toll-like receptor activation. / Chan, Amy; Alikhan, Maliha; Odobasic, Dragana; Gan, Poh Yi; Khouri, Mary; Steinmetz, Oliver; Mansell, Ashley Scott; Kitching, Arthur Richard; Holdsworth, Stephen Roger; Summers, Shaun Andrew.

In: American Journal of Pathology, Vol. 184, No. 5, 2014, p. 1411 - 1418.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Innate IL-17A-producing leukocytes promote acute kidney injury via inflammasome and Toll-like receptor activation

AU - Chan, Amy

AU - Alikhan, Maliha

AU - Odobasic, Dragana

AU - Gan, Poh Yi

AU - Khouri, Mary

AU - Steinmetz, Oliver

AU - Mansell, Ashley Scott

AU - Kitching, Arthur Richard

AU - Holdsworth, Stephen Roger

AU - Summers, Shaun Andrew

PY - 2014

Y1 - 2014

N2 - 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 Rorgammat(-/-) mice, as well as in mice treated pre-emptively with anti-IL-17A antibodies. Both renal injury and renal IL-1beta 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-1beta 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 gammadelta T cells, IL-17A from those cells does not contribute to renal injury. Cisplatin-induced injury was unchanged in gammadelta 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.

AB - 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 Rorgammat(-/-) mice, as well as in mice treated pre-emptively with anti-IL-17A antibodies. Both renal injury and renal IL-1beta 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-1beta 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 gammadelta T cells, IL-17A from those cells does not contribute to renal injury. Cisplatin-induced injury was unchanged in gammadelta 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.

UR - http://www.sciencedirect.com/science/article/pii/S0002944014000984

U2 - 10.1016/j.ajpath.2014.01.023

DO - 10.1016/j.ajpath.2014.01.023

M3 - Article

VL - 184

SP - 1411

EP - 1418

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

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