| First Author | Di Gregoli K | Year | 2020 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 40 |
| Issue | 6 | Pages | 1491-1509 |
| PubMed ID | 32295421 | Mgi Jnum | J:292467 |
| Mgi Id | MGI:6448812 | Doi | 10.1161/ATVBAHA.120.314252 |
| Citation | Di Gregoli K, et al. (2020) Galectin-3 Identifies a Subset of Macrophages With a Potential Beneficial Role in Atherosclerosis. Arterioscler Thromb Vasc Biol 40(6):1491-1509 |
| abstractText | 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)-beta1 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. |
