IL-33, a member of the IL-1 family, acts as an alarmin in immune responses. Epithelial-mesenchymal
transition 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, 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 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-βRs, 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.
Graphical abstract
Graphical Abstract
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Article info
Publication history
Published online: May 24, 2023
Accepted:
May 9,
2023
Publication stage
In Press Journal Pre-ProofFootnotes
Supported by the National Natural Science Foundation of China grants 82071849 and 81871241 (H.Z.).
X.Z., J.L., J.R., D.R., and M.G. contributed equally to this work.
Disclosures: None declared.
Identification
Copyright
© 2023 Published by Elsevier Inc. on behalf of the American Society for Investigative Pathology.
