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Lookup NU author(s): Dr Lee Borthwick
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024 The AuthorsIntegrin-mediated activation of the profibrotic mediator transforming growth factor-β1 (TGF-β1), plays a critical role in idiopathic pulmonary fibrosis (IPF) pathogenesis. Galectin-3 is believed to contribute to the pathological wound healing seen in IPF, although its mechanism of action is not precisely defined. We hypothesized that galectin-3 potentiates TGF-β1 activation and/or signaling in the lung to promote fibrogenesis. We show that galectin-3 induces TGF-β1 activation in human lung fibroblasts (HLFs) and specifically that extracellular galectin-3 promotes oleoyl-L-α-lysophosphatidic acid sodium salt–induced integrin-mediated TGF-β1 activation. Surface plasmon resonance analysis confirmed that galectin-3 binds to αv integrins, αvβ1, αvβ5, and αvβ6, and to the TGFβRII subunit in a glycosylation-dependent manner. This binding is heterogeneous and not a 1:1 binding stoichiometry. Binding interactions were blocked by small molecule inhibitors of galectin-3, which target the carbohydrate recognition domain. Galectin-3 binding to β1 integrin was validated in vitro by coimmunoprecipitation in HLFs. Proximity ligation assays indicated that galectin-3 and β1 integrin colocalize closely (≤40 nm) on the cell surface and that colocalization is increased by TGF-β1 treatment and blocked by galectin-3 inhibitors. In the absence of TGF-β1 stimulation, colocalization was detectable only in HLFs from IPF patients, suggesting the proteins are inherently more closely associated in the disease state. Galectin-3 inhibitor treatment of precision cut lung slices from IPF patients’ reduced Col1a1, TIMP1, and hyaluronan secretion to a similar degree as TGF-β type I receptor inhibitor. These data suggest that galectin-3 promotes TGF-β1 signaling and may induce fibrogenesis by interacting directly with components of the TGF-β1 signaling cascade.
Author(s): Calver JF, Parmar NR, Harris G, Lithgo RM, Stylianou P, Zetterberg FR, Gooptu B, Mackinnon AC, Carr SB, Borthwick LA, Scott DJ, Stewart ID, Slack RJ, Jenkins RG, John AE
Publication type: Article
Publication status: Published
Journal: Journal of Biological Chemistry
Year: 2024
Volume: 300
Issue: 6
Print publication date: 01/06/2024
Online publication date: 18/04/2024
Acceptance date: 29/03/2024
Date deposited: 29/05/2024
ISSN (print): 0021-9258
ISSN (electronic): 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology Inc.
URL: https://doi.org/10.1016/j.jbc.2024.107300
DOI: 10.1016/j.jbc.2024.107300
PubMed id: 38641066
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