AI Article Synopsis
- IL-33 is identified as an alarmin that plays a crucial role in immune response and is linked to the development of renal interstitial fibrosis.
- The study found increased levels of IL-33 and its receptor IL1RL1 (ST2) in human fibrotic kidney tissues, while IL-33 or ST2-deficient mice showed reduced markers associated with fibrosis.
- In HK-2 cells, IL-33 enhances TGF-β receptor signaling, leading to increased extracellular matrix production and reduced E-cadherin levels, suggesting that IL-33 and TGF-β signaling work together to promote renal fibrosis.
- Targeting the IL-33/ST2 pathway could offer a promising therapeutic approach for treating renal fibrosis.
Article Abstract
IL-33, a member of the IL-1 family, acts as an alarmin in immune response. Epithelial-mesenchymal transition and transforming growth factor-β (TGF-β)–induced fibroblast activation are key events in the development of renal interstitial fibrosis. The current study found increased expression of IL-33 and interleukin-1 receptor-like 1 (IL1RL1, alias 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, and vimentin, and increased E-cadherin levels. In HK-2 cells, IL-33 promotes the phosphorylation of the TGF-β receptor (TGF-βR), Smad2, and Smad3, and the production of extracellular matrix (ECM), with reduced expression of E-cadherin. Blocking TGF-βR signaling or suppressing ST2 expression impeded 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 induced a proximate interaction between ST2 and TGF-βRs, activating downstream Smad2 and Smad3 for ECM production in renal epithelial cells. Collectively, this 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.
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| http://dx.doi.org/10.1016/j.ajpath.2023.05.002 | DOI Listing |
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