IL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in Renal Inflammation and Fibrosis

Chi, Hsi-HuaHsi-HuaChiHua, Kuo-FengKuo-FengHuaLin, Yu-ChuanYu-ChuanLinCHING-LIANG CHUHsieh, Chih-YuChih-YuHsiehHsu, Yu-JueiYu-JueiHsuKa, Shuk-ManShuk-ManKaTsai, Yu-LingYu-LingTsaiLiu, Feng-ChengFeng-ChengLiuChen, AnnAnnChen2019-07-232019-07-232017-071046-6673http://www.scopus.com/inward/record.url?eid=2-s2.0-85021712319&partnerID=MN8TOARShttps://scholars.lib.ntu.edu.tw/handle/123456789/414593IL-36 cytokines are proinflammatory and have an important role in innate and adaptive immunity, but the role of IL-36 signaling in renal tubulointerstitial lesions (TILs), a major prognostic feature of renal inflammation and fibrosis, remains undetermined. In this study, increased IL-36α expression detected in renal biopsy specimens and urine samples from patients with renal TILs correlated with renal function impairment. We confirmed the increased expression of IL-36α in the renal tubular epithelial cells of a mouse model of unilateral ureteral obstruction (UUO) and related cell models using mechanically induced pressure, oxidative stress, or high mobility group box 1. In contrast, the kidneys of IL-36 receptor (IL-36R) knockout mice exhibit attenuated TILs after UUO. Compared with UUO-treated wild-type mice, UUO-treated IL-36 knockout mice exhibited markedly reduced NLRP3 inflammasome activation and macrophage/T cell infiltration in the kidney and T cell activation in the renal draining lymph nodes. In vitro, recombinant IL-36α facilitated NLRP3 inflammasome activation in renal tubular epithelial cells, macrophages, and dendritic cells and enhanced dendritic cell-induced T cell proliferation and Th17 differentiation. Furthermore, deficiency of IL-23, which was diminished in IL-36R knockout UUO mice, also reduced renal TIL formation in UUO mice. In wild-type mice, administration of an IL-36R antagonist after UUO reproduced the results obtained in UUO-treated IL-36R knockout mice. We propose that IL-36 signaling contributes to the pathogenesis of renal TILs through the activation of the NLRP3 inflammasome and IL-23/IL-17 axis.enIL-36 receptor; IL-36 receptor antagonist; IL-36α; knockout mice; patients’ samples; unilateral ureteral obstructionIL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in Renal Inflammation and Fibrosisjournal article10.1681/ASN.2016080840281794332-s2.0-85021712319WOS:000404568700011https://api.elsevier.com/content/abstract/scopus_id/85021712319