1. Academic Validation
  2. Crosstalk between ST2 and TGF-β Receptor Signaling Promotes Renal Fibrosis

Crosstalk between ST2 and TGF-β Receptor Signaling Promotes Renal Fibrosis

  • Am J Pathol. 2023 May 24;S0002-9440(23)00172-4. doi: 10.1016/j.ajpath.2023.05.002.
Xingxing Zhu 1 Jiahui Lu 2 Jia Rao 3 Dongqing Ru 4 Mengru Gao 5 Dongyan Shi 2 Kelei Cao 2 Shuang Wen 2 Chunsun Dai 6 Xuerong Wang 7 Wenli Mi 8 Lixin Liu 9 Hong Zhou 10
Affiliations

Affiliations

  • 1 Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: xxzhu@njmu.edu.cn.
  • 2 Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 3 Department of Immunology, Anhui Medical University, Hefei, Anhui, China.
  • 4 Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu, China; Central Laboratory, The Second Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan, China.
  • 5 Center for Kidney Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 6 Department of Clinical Pathology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.
  • 7 Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 8 Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 9 Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
  • 10 Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu, China; Department of Immunology, Anhui Medical University, Hefei, Anhui, China. Electronic address: hzhou@ahmu.edu.cn.
Abstract

Interleukin (IL)-33, a member of the IL-1 family, acts as an "alarmin" in immune responses. Epithelial-mesenchymal transition (EMT) and Transforming Growth Factor-β (TGF-β)-induced fibroblast activation are key events in the development of renal interstitial fibrosis. We found increased expression of IL-33 and ST2, the receptor for IL-33, in human fibrotic renal tissues. In addition, IL-33- or ST2-deficient mice showed significantly reduced levels of fibronectin, α-smooth muscle actin (α-SMA), and vimentin, and increased E-cadherin levels. In HK-2 cells, IL-33 promotes the phosphorylation of the TGF-β Receptor, SMAD2, and SMAD3, and the production of extracellular matrix (ECM), with reduced expression of E-cadherin. Blocking TGF-β Receptor signaling or suppressing ST2 expression impedes SMAD2 and SMAD3 phosphorylation, thereby reducing ECM production, suggesting that IL-33-induced ECM synthesis requires cooperation between the two pathways. Mechanistically, IL-33 treatment induces a proximate interaction between ST2 and TGF-β receptors, activating downstream SMAD2 and SMAD3 for ECM production in renal epithelial cells. Collectively, our study identified a novel and essential role for IL-33 in promoting TGF-β signaling and ECM production in the development of renal fibrosis. Therefore, targeting IL-33/ST2 signaling may be an effective therapeutic strategy for renal fibrosis.

Keywords

IL-33; ST2; TGF-β; extracellular matrix protein; renal fibrosis.

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