IL-36 Signaling Facilitates Activation of the NLRP3 Inflammasome and IL-23/IL-17 Axis in Renal Inflammation and Fibrosis.
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-36αexpression 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-36αin 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-36αfacilitated 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.
Graduate Institutes of Life Sciences and.
Hsi-Hua
HH
Chi
Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan; and.
Kuo-Feng
KF
Hua
Graduate Institutes of Life Sciences and.
Yu-Chuan
YC
Lin
Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, Taiwan.
Ching-Liang
CL
Chu
Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan; and.
Chih-Yu
CY
Hsieh
Division of Nephrology, Department of Medicine.
Yu-Juei
YJ
Hsu
Graduate Institutes of Life Sciences and shukmanka@gmail.com annchen31717@gmail.com.|Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan.
Shuk-Man
SM
Ka
Graduate Institutes of Life Sciences and.
Yu-Ling
YL
Tsai
Division of Rheumatology/Immunology and Allergy, Department of Medicine, and.
Feng-Cheng
FC
Liu
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; shukmanka@gmail.com annchen31717@gmail.com.
Ann
A
Chen
D000818:Animals; D005355:Fibrosis / Q000209:etiology; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D007375:Interleukin-1 / Q000502:physiology*; D020381:Interleukin-17 / Q000502:physiology*; D053759:Interleukin-23 / Q000502:physiology*; D007668:Kidney / Q000473:pathology*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology*; D009393:Nephritis / Q000209:etiology*; D015398:Signal Transduction; D014517:Ureteral Obstruction / Q000209:etiology
C508717:IL17A protein, human; C508586:IL36A protein, human; D058847:Inflammasomes; D007375:Interleukin-1; D020381:Interleukin-17; D053759:Interleukin-23; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C543716:interleukin 1F6, mouse
IL-36 receptor; IL-36 receptor antagonist; IL-36α; knockout mice; patients’ samples; unilateral ureteral obstruction