Innate IL-17A-producing leukocytes promote acute kidney injury via inflammasome and Toll-like receptor activation
Standard
Innate IL-17A-producing leukocytes promote acute kidney injury via inflammasome and Toll-like receptor activation. / Chan, Amy J; Alikhan, Maliha A; Odobasic, Dragana; Gan, Poh Y; Khouri, Mary B; Steinmetz, Oliver M; Mansell, Ashley S; Kitching, A Richard; Holdsworth, Stephen R; Summers, Shaun A.
in: AM J PATHOL, Jahrgang 184, Nr. 5, 01.05.2014, S. 1411-1418.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Innate IL-17A-producing leukocytes promote acute kidney injury via inflammasome and Toll-like receptor activation
AU - Chan, Amy J
AU - Alikhan, Maliha A
AU - Odobasic, Dragana
AU - Gan, Poh Y
AU - Khouri, Mary B
AU - Steinmetz, Oliver M
AU - Mansell, Ashley S
AU - Kitching, A Richard
AU - Holdsworth, Stephen R
AU - Summers, Shaun A
N1 - Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PY - 2014/5/1
Y1 - 2014/5/1
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 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.
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 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.
U2 - 10.1016/j.ajpath.2014.01.023
DO - 10.1016/j.ajpath.2014.01.023
M3 - SCORING: Journal article
C2 - 24631024
VL - 184
SP - 1411
EP - 1418
JO - AM J PATHOL
JF - AM J PATHOL
SN - 0002-9440
IS - 5
ER -