title: IL-33 exacerbates acute kidney injury.
abstract: Inflammation contributes to the pathogenesis of acute kidney injury (AKI). IL-33 is a proinflammatory cytokine, but its role in AKI is unknown. Here we observed increased protein expression of full-length IL-33 in the kidney following induction of AKI with cisplatin. To determine whether IL-33 promotes injury, we administered soluble ST2 (sST2), a fusion protein that neutralizes IL-33 activity by acting as a decoy receptor. Compared with cisplatin-induced AKI in untreated mice, mice treated with sST2 had fewer CD4 T cells infiltrate the kidney, lower serum creatinine, and reduced acute tubular necrosis (ATN) and apoptosis. In contrast, administration of recombinant IL-33 (rIL-33) exacerbated cisplatin-induced AKI, measured by an increase in CD4 T cell infiltration, serum creatinine, ATN, and apoptosis; this did not occur in CD4-deficient mice, suggesting that CD4 T cells mediate the injurious effect of IL-33. Wildtype mice that received cisplatin and rIL-33 also had higher levels of the proinflammatory chemokine CXCL1, which CD T cells produce, in the kidney compared with CD4-deficient mice. Mice deficient in the CXCL1 receptor also had lower serum creatinine, ATN, and apoptosis than wildtype mice following cisplatin-induced AKI. Taken together, IL-33 promotes AKI through CD4 T cell-mediated production of CXCL1. These data suggest that inhibiting IL-33 or CXCL1 may have therapeutic potential in AKI.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado at Denver, Aurora, CO 80262, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Akcay
authors.forename: Quocan
authors.initials: Q
authors.lastname: Nguyen
authors.forename: Zhibin
authors.initials: Z
authors.lastname: He
authors.forename: Kultigin
authors.initials: K
authors.lastname: Turkmen
authors.forename: Dong
authors.initials: D
authors.lastname: Won Lee
authors.forename: Ana Andres
authors.initials: AA
authors.lastname: Hernando
authors.forename: Christopher
authors.initials: C
authors.lastname: Altmann
authors.forename: Aysun
authors.initials: A
authors.lastname: Toker
authors.forename: Arijana
authors.initials: A
authors.lastname: Pacic
authors.forename: Danica Galesic
authors.initials: DG
authors.lastname: Ljubanovic
authors.forename: Alkesh
authors.initials: A
authors.lastname: Jani
authors.forename: Sarah
authors.initials: S
authors.lastname: Faubel
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D000067596:Interleukin-33; D007378:Interleukins / Q000097:blood / Q000276:immunology* / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000970:Antineoplastic Agents; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D007378:Interleukins; D002945:Cisplatin