Galectin-3 Expression and Secretion Links Macrophages to the Promotion of Renal Fibrosis
Open accessAbstract
Macrophages have been proposed as a key cell type in the pathogenesis of renal fibrosis; however, the mechanism by which macrophages drive fibrosis is still unclear. We show that expression of galectin-3, a beta-galactoside-binding lectin, is up-regulated in a mouse model of progressive renal fibrosis (unilateral ureteric obstruction, UUO), and absence of galectin-3 protects against renal myofibroblast accumulation/activation and fibrosis. Furthermore, specific depletion of macrophages using CD11b-DTR mice reduces fibrosis severity after UUO demonstrating that macrophages are key cells in the pathogenesis of renal fibrosis. Disruption of the galectin-3 gene does not affect macrophage recruitment after UUO, or macrophage proinflammatory cytokine profiles in response to interferon-gamma/lipopolysaccharide. In addition, absence of galectin-3 does not affect transforming growth factor-beta expression or Smad 2/3 phosphorylation in obstructed kidneys. Adoptive transfer of wild-type but not galectin-3(-/-) macrophages did, however, restore the fibrotic phenotype in galectin-3(-/-) mice. Cross-over experiments using wild-type and galectin-3(-/-) macrophage supernatants and renal fibroblasts confirmed that secretion of galectin-3 by macrophages is critical in the activation of renal fibroblasts to a profibrotic phenotype. Therefore, we demonstrate for the first time that galectin-3 expression and secretion by macrophages is a major mechanism linking macrophages to the promotion of renal fibrosis.
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The αv-containing integrins αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8 bind to the latency-associated peptide (LAP) of TGF-β1.
“the integrins αvβ1, αvβ3, αvβ5, αvβ6 and αvβ8 have all been shown to bind to an N-terminal fragment of the TGFβ1 gene product called the latency associated peptide (LAP)”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [91]
LAP normally forms a noncovalent latent complex with active TGF-β, preventing TGF-β from binding its receptors and inducing biological effects.
“which normally forms a noncovalent complex (latent complex) with the active cytokine, preventing TGF-β from binding to its cognate receptors and inducing biological effects89–93”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [91]
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- Authors
- Henderson, N. C., Mackinnon, A. C., Farnworth, S. L., Kipari, T., Haslett, C., Iredale, J. P., Liu, F.-T., Hughes, J., & Sethi, T.
- Affiliations
- Centre for Inflammation Research (GB)
- University of California Davis Medical Center (US)
- Corresponding author
- Sethi, Tariq
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 172
- Issue
- 2
- Pages
- 288-298
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC2312353
- OpenAlex
- W2102815431
- Cited by
- 562
- References
- 52
- Citations by year
- 2026: 21 · 2025: 26 · 2024: 39 · 2023: 34 · 2022: 29 · 2021: 40 · 2020: 31 · 2019: 26 · 2018: 31 · 2017: 27 · 2016: 46 · 2015: 35 · 2014: 47 · 2013: 32 · 2012: 41
- FWCI
- 8.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Galectins and Cancer Biology
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Keywords
- galectin-3, macrophages, renal fibrosis, unilateral ureteral obstruction, myofibroblast activation, macrophage depletion, adoptive transfer, fibroblast activation, beta-galactoside-binding lectin, Smad2/3 signaling, TGF-beta
- MeSH terms
- Animals, Fibroblasts, Fibrosis, Fluorescent Antibody Technique, Immunohistochemistry, Kidney, Macrophages, Ureteral Obstruction, Blotting, Western, Gene Expression, Adoptive Transfer, Reverse Transcriptase Polymerase Chain Reaction, Galectin 3, Mice
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