IL-33/ST2 axis mediates hyperplasia of intrarenal urothelium in obstructive renal injury

다국어 초록 (Multilingual Abstract)

The monolayered intrarenal urothelium covers the renal papilla and ureteropelvic junction (UPJ). In response to increased renal pressure during obstruction or ischemic injuries, intrarenal urothelial cells begin to proliferate and form a multilayered urothelium. Little is known regarding the mechanism and pathophysiological role of urothelium hyperplasia during renal obstruction. In this study, we investigated the expression of interleukin (IL)-33, an IL-1 family cytokine, in kidneys with unilateral ureteral obstruction (UUO)-induced obstructive injury. IL-33 levels in hydronephrotic urine and serum were upregulated 2 days after UUO. The number of ST2-expressing immune cells was increased in the UUO kidney. We found that IL-33 was upregulated in vimentin-positive cells in the cortical and medullar layers and the UPJ stroma. Moreover, IL-33 expression was predominantly induced in multilayered keratin 5- positive urothelial cells in the UPJ. IL-33 was not detected in terminally differentiated superficial umbrella cells expressing uroplakin 3a. In vivo, we confirmed that deficiency of IL33 or its receptor ST2 attenuated UUO-induced hyperplasia of the UPJ urothelium. Deficiency of IL33 attenuated the expression of UUO-induced type 2 inflammatory cytokines and upregulated uroplakins and urothelial differentiation signaling in UPJ tissues. Our results collectively suggest that the IL-33/ST2 axis mediates the activation of innate immune responses and contributes to urothelial hyperplasia by regulating urothelial differentiation in obstructive kidney injury.

참고문헌 (Reference)

1 David J. DeGraff, "When urothelial differentiation pathways go wrong: Implications for bladder cancer development and progression" Elsevier BV 31 (31): 802-811, 2013

2 Alexey Girshovich, "Ureteral obstruction promotes proliferation and differentiation of the renal urothelium into a bladder-like phenotype" Elsevier BV 82 (82): 428-435, 2012

3 Robert L. Chevalier, "Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy" Elsevier BV 75 (75): 1145-1152, 2009

4 Wei-Yu Chen, "Upregulation of Interleukin-33 in obstructive renal injury" Elsevier BV 473 (473): 1026-1032, 2016

5 Kazunari Sugita, "Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients" Elsevier BV 141 (141): 300-310.e11, 2018

6 Levent Demirtas, "The possible role of interleukin-33 as a new player in the pathogenesis of contrast-induced nephropathy in diabetic rats" Informa UK Limited 38 (38): 952-960, 2016

7 Marjorie De la Fuente, "The IL-33/ST2 axis: Role in health and disease" Elsevier BV 26 (26): 615-623, 2015

8 Antoine Thierry, "The Alarmin Concept Applied to Human Renal Transplantation: Evidence for a Differential Implication of HMGB1 and IL-33" Public Library of Science (PLoS) 9 (9): e88742-, 2014

9 B. D. Abbott, "TCDD-Induced hyperplasia of the ureteral epithelium produces hydronephrosis in murine fetuses" Wiley 35 (35): 329-334, 1987

10 Caporali, A., "Soluble ST2 is regulated by p75 neurotrophin receptor and predicts mortality in diabetic patients with critical limb ischemia" 32 : e149-e160, 2012

11 Zarine R. Balsara, "Sleeping beauty: awakening urothelium from its slumber" American Physiological Society 312 (312): F732-F743, 2017

12 Saulo Klahr, "Obstructive nephropathy and renal fibrosis" American Physiological Society 283 (283): F861-F875, 2002

13 Karl S. Roth, "Obstructive Uropathy: An Important Cause of Chronic Renal Failure in Children" SAGE Publications 41 (41): 309-314, 2016

14 Wei-Yu Chen, "Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33" Proceedings of the National Academy of Sciences 112 (112): 7249-7254, 2015

15 Onk, D., "Melatonin attenuates contrast-induced nephropathy in diabetic rats: the role of interleukin-33 and oxidative stress" 2016 : 9050828-, 2016

16 David J. DeGraff, "Loss of the Urothelial Differentiation Marker FOXA1 Is Associated with High Grade, Late Stage Bladder Cancer and Increased Tumor Proliferation" Public Library of Science (PLoS) 7 (7): e36669-, 2012

17 Sedat Caner, "Is IL-33 useful to detect early stage of renal failure?" Informa UK Limited 36 (36): 78-80, 2013

18 Yuan-Yow Chiou, "Intrinsic expression of Th2 cytokines in urothelium of congenital ureteropelvic junction obstruction" Elsevier BV 67 (67): 638-646, 2005

19 C. Vinsonneau, "Intrarenal urothelium proliferation: an unexpected early event following ischemic injury" American Physiological Society 299 (299): F479-F486, 2010

20 Clare Hardman, "Interleukin-33, friend and foe in type-2 immune responses" Elsevier BV 42 : 16-24, 2016

21 Nikolas T Martin, "Interleukin 33 is a guardian of barriers and a local alarmin" Springer Nature 17 (17): 122-131, 2016

22 Hye Young Kim, "Innate lymphoid cells responding to IL-33 mediate airway hyperreactivity independently of adaptive immunity" Elsevier BV 129 (129): 216-227.e6, 2012

23 Laurel A Monticelli, "Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus" Springer Nature 12 (12): 1045-1054, 2011

24 Ya-Jen Chang, "Innate lymphoid cells mediate influenza-induced airway hyper-reactivity independently of adaptive immunity" Springer Nature 12 (12): 631-638, 2011

25 Jan-Hendrik Riedel, "IL-33–Mediated Expansion of Type 2 Innate Lymphoid Cells Protects from Progressive Glomerulosclerosis" American Society of Nephrology (ASN) 28 (28): 2068-2080, 2017

26 Gregory D. Rak, "IL-33-Dependent Group 2 Innate Lymphoid Cells Promote Cutaneous Wound Healing" Elsevier BV 136 (136): 487-496, 2016

27 Thomas R. Shelite, "IL-33-Dependent Endothelial Activation Contributes to Apoptosis and Renal Injury in Orientia tsutsugamushi-Infected Mice" Public Library of Science (PLoS) 10 (10): e0004467-, 2016

28 Ryba-Stanislawowska, M, "IL-33 effect on quantitative changes of CD4+CD25highFOXP3+ regulatory T cells in children with type 1 diabetes" 2016 : 9429760-, 2016

29 FEIFEI YANG, "IL-33 and kidney disease (Review)" Spandidos Publications 13 (13): 3-8, 2016

30 Ali Akcay, "IL-33 Exacerbates Acute Kidney Injury" American Society of Nephrology (ASN) 22 (22): 2057-2067, 2011

31 Vuvi G. Tran, "IL-33 Enhances Host Tolerance to Candida albicans Kidney Infections through Induction of IL-13 Production by CD4 + T Cells" The American Association of Immunologists 194 (194): 4871-4879, 2015

32 Deepti R. Nagarkar, "IL-13 mediates IL-33–dependent mast cell and type 2 innate lymphoid cell effects on bronchial epithelial cells" Elsevier BV 136 (136): 202-205, 2015

33 Kunyoo Shin, "Hedgehog Signaling Restrains Bladder Cancer Progression by Eliciting Stromal Production of Urothelial Differentiation Factors" Elsevier BV 26 (26): 521-533, 2014

34 Tammer Yamany, "Formation and regeneration of the urothelium" Ovid Technologies (Wolters Kluwer Health) 19 (19): 323-330, 2014

35 Michael S. Forbes, "Fight-or-flight: murine unilateral ureteral obstruction causes extensive proximal tubular degeneration, collecting duct dilatation, and minimal fibrosis" American Physiological Society 303 (303): F120-F129, 2012

36 P. Baumgart, "Epithelial Abnormalities in the Renal Pelvis in Experimental Hydronephrosis and Pyelonephritis" Elsevier BV 176 (176): 185-195, 1983

37 Chen, W. Y, "Emerging roles of IL-33/ST2 axis in renal diseases" 18 : 2017

38 Bruhs, A, "Disruption of the epidermal barrier induces regulatory T cells via IL-33 in mice" 16 : 2017

39 Hiroyuki Iwahana, "Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells" Wiley 264 (264): 397-406, 1999

40 K. Yasuda, "Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice" Proceedings of the National Academy of Sciences 109 (109): 3451-3456, 2012

41 Yu-Shi Bao, "Characterization of Interleukin-33 and Soluble ST2 in Serum and Their Association with Disease Severity in Patients with Chronic Kidney Disease" Springer Nature 32 (32): 587-594, 2012

42 Andrew P. Evan, "Calcium oxalate crystal localization and osteopontin immunostaining in genetic hypercalciuric stone-forming rats" Elsevier BV 65 (65): 154-161, 2004

43 Yen-Rei A. Yu, "A Protocol for the Comprehensive Flow Cytometric Analysis of Immune Cells in Normal and Inflamed Murine Non-Lymphoid Tissues" Public Library of Science (PLoS) 11 (11): e0150606-, 2016