Galectin-3 Identifies a Subset of Macrophages With a Potential Beneficial Role in Atherosclerosis
Karina Di Gregoli, Michelle Somerville, Rosaria Bianco, Anita C. Thomas, Aleksandra Frankow, Andrew C. Newby, Sarah J. George, Christopher L. Jackson, Jason L. Johnson
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 macrophages within advanced human, rabbit, and mouse plaques compared with early lesions. Interestingly, statin treatment reduced galectin-3–negative macrophage accrual in advanced plaques within hypercholesterolemic (apolipoprotein E deficient) Apoe −/− mice. Accordingly, compared with 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 proinflammatory genes including MMP (matrix metalloproteinase)-12, CCL2 (chemokine [C-C motif] ligand 2), PTGS2 (prostaglandin-endoperoxide synthase 2), and IL (interleukin)-6, alongside reduced TGF (transforming growth factor)-β1 expression and consequent SMAD signaling. Moreover, we found that MMP12 cleaves macrophage cell-surface galectin-3 resulting in the appearance of a 22-kDa 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 proinflammatory macrophage polarization. Moreover, galectin-3–positive macrophages were more abundant within plaques of Mmp12 −/− : Apoe −/− mice compared with Mmp12 +/+ : Apoe −/− animals. Conclusions: This study reveals a prominent protective role for galectin-3 in regulating macrophage polarization and invasive capacity and, therefore, delaying plaque progression.