PMID- 28179433 OWN - NLM STAT- MEDLINE DCOM- 20170829 LR - 20221109 IS - 1533-3450 (Electronic) IS - 1046-6673 (Print) IS - 1046-6673 (Linking) VI - 28 IP - 7 DP - 2017 Jul TI - IL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in Renal Inflammation and Fibrosis. PG - 2022-2037 LID - 10.1681/ASN.2016080840 [doi] AB - IL-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-36alpha 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-36alpha 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-36alpha 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. CI - Copyright (c) 2017 by the American Society of Nephrology. FAU - Chi, Hsi-Hua AU - Chi HH AD - Graduate Institutes of Life Sciences and. FAU - Hua, Kuo-Feng AU - Hua KF AD - Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan; and. FAU - Lin, Yu-Chuan AU - Lin YC AD - Graduate Institutes of Life Sciences and. FAU - Chu, Ching-Liang AU - Chu CL AD - Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan. FAU - Hsieh, Chih-Yu AU - Hsieh CY AD - Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan; and. FAU - Hsu, Yu-Juei AU - Hsu YJ AD - Division of Nephrology, Department of Medicine. FAU - Ka, Shuk-Man AU - Ka SM AD - Graduate Institutes of Life Sciences and shukmanka@gmail.com annchen31717@gmail.com. AD - Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan. FAU - Tsai, Yu-Ling AU - Tsai YL AD - Graduate Institutes of Life Sciences and. FAU - Liu, Feng-Cheng AU - Liu FC AD - Division of Rheumatology/Immunology and Allergy, Department of Medicine, and. FAU - Chen, Ann AU - Chen A AD - Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; shukmanka@gmail.com annchen31717@gmail.com. LA - eng PT - Journal Article DEP - 20170208 PL - United States TA - J Am Soc Nephrol JT - Journal of the American Society of Nephrology : JASN JID - 9013836 RN - 0 (IL17A protein, human) RN - 0 (IL36A protein, human) RN - 0 (Inflammasomes) RN - 0 (Interleukin-1) RN - 0 (Interleukin-17) RN - 0 (Interleukin-23) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (NLRP3 protein, human) RN - 0 (Nlrp3 protein, mouse) RN - 0 (interleukin 1F6, mouse) SB - IM MH - Animals MH - Fibrosis/etiology MH - Humans MH - Inflammasomes/*physiology MH - Interleukin-1/*physiology MH - Interleukin-17/*physiology MH - Interleukin-23/*physiology MH - Kidney/*pathology MH - Mice MH - NLR Family, Pyrin Domain-Containing 3 Protein/*physiology MH - Nephritis/*etiology MH - *Signal Transduction MH - Ureteral Obstruction/etiology PMC - PMC5491282 OTO - NOTNLM OT - IL-36 receptor OT - IL-36 receptor antagonist OT - IL-36alpha OT - knockout mice OT - patients' samples OT - unilateral ureteral obstruction EDAT- 2017/02/10 06:00 MHDA- 2017/08/30 06:00 PMCR- 2018/07/01 CRDT- 2017/02/10 06:00 PHST- 2016/08/04 00:00 [received] PHST- 2017/01/04 00:00 [accepted] PHST- 2017/02/10 06:00 [pubmed] PHST- 2017/08/30 06:00 [medline] PHST- 2017/02/10 06:00 [entrez] PHST- 2018/07/01 00:00 [pmc-release] AID - ASN.2016080840 [pii] AID - 2016080840 [pii] AID - 10.1681/ASN.2016080840 [doi] PST - ppublish SO - J Am Soc Nephrol. 2017 Jul;28(7):2022-2037. doi: 10.1681/ASN.2016080840. Epub 2017 Feb 8.