Galectin-3 identifies a subset of macrophages with a potential beneficial role in atherosclerosis: Macrophage galectin-3 prevents plaque progression

Karina Di Gregoli, Michelle Somerville, Rosaria Bianco, Anita C Thomas, Aleksandra Frankow, Andrew C Newby, Sarah J George, Christopher L Jackson, Jason L Johnson*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Objective: Galectin-3 (formerly known as Mac-2), encoded by the LGALS3 gene, is proposed to regulate macrophage adhesion, chemotaxis, and apoptosis. We investigated the role of galectin-3 in determining the inflammatory profile of macrophages and composition of atherosclerotic plaques.

Approach and Results: We observed increased accumulation of galectin-3 negative (galectin-3-ve) macrophages within advanced human, rabbit and mouse plaques compared to early lesions. Interestingly, statin treatment reduced galectin-3-ve macrophage accrual in advanced plaques within hypercholesterolaemic (apolipoprotein E-deficient) Apoe-/- mice. Accordingly, compared to Lgals3+/+:Apoe-/- mice, Lgals3-/-:Apoe-/- mice displayed altered plaque composition through increased macrophage:smooth muscle cell ratio, reduced collagen content and increased necrotic core area, characteristics of advanced plaques in humans. Additionally, macrophages from Lgals3-/- mice exhibited increased invasive capacity in vitro and in vivo. Furthermore, loss of galectin-3 in vitro and in vivo was associated with increased expression of pro-inflammatory genes including matrix metalloproteinase12 (MMP12), chemokine (C-C motif) ligand 2 (CCL2), prostaglandin-endoperoxide synthase 2 (PTGS2) and interleukin-6 (IL6), alongside reduced transforming growth factor beta 1 (TGFB1) expression and consequent SMAD signalling. Moreover, we found that MMP12 cleaves macrophage cell-surface galectin-3 resulting in the appearance of a 22kDa fragment whereas plasma levels of galectin-3 were reduced in Mmp12-/-:Apoe-/- mice, highlighting a novel mechanism where MMP12-dependent cleavage of galectin-3 promotes pro-inflammatory macrophage polarisation. Moreover, galectin-3 positive macrophages were more abundant within plaques of Mmp12-/-:Apoe-/- mice compared to Mmp12+/+:Apoe-/- animals.

Conclusions: This study reveals a prominent protective role for Galectin-3 in regulating macrophage polarisation and invasive capacity, and therefore delaying plaque progression.
Original languageEnglish
Pages (from-to)1491-1509
Number of pages19
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume40
Early online date16 Apr 2020
DOIs
Publication statusPublished - 28 May 2020

Keywords

  • Atherosclerosis
  • Macrophage
  • macrophage polarization
  • Matrix metalloproteases (MMPs)
  • fibrosis

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