2. Academic Validation
  3. 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.
PMID: 37236504 DOI: 10.1016/j.ajpath.2023.05.002
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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