Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization

• Published in: International journal of molecular sciences Vol. 21; no. 15; p. 5511
• Main Authors: Lin, En-Shyh, Hsu, Yu-An, Chang, Ching-Yao, Lin, Hui-Ju, Chen, Chih Sheng, Wan, Lei
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.07.2020; MDPI
• Subjects: ABCA1 protein; Ablation; Adipocytes; Animals; Arteriosclerosis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; ATP Binding Cassette Transporter 1 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 1 - genetics; ATP-binding protein; Binding; CD163 antigen; CD36 antigen; CD36 Antigens - genetics; Cell Cycle Proteins - genetics; Cell Polarity - genetics; Chemokines; Cholesterol; Chronic illnesses; Coronary vessels; Cytokines; Disease Models, Animal; Doxycycline; foam cell; Foam Cells - metabolism; Foam Cells - pathology; galectin-12; Galectins - genetics; Gene expression; Gene Expression Regulation - genetics; Glucose; Humans; Inflammation; Insulin; Interleukin 6; Kinases; Lipids; Lipolysis; Lipoproteins, LDL - genetics; Lipoproteins, LDL - metabolism; Low density lipoprotein; macrophage polarization; Macrophages; Macrophages - metabolism; Macrophages - pathology; Mice; Mice, Knockout; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Pathogenesis; Polarization; Receptors, LDL - genetics; Scavenger receptors; Scavenger Receptors, Class B - genetics; Tumor necrosis factor-α; atherosclerosis; foam cell; macrophage polarization; galectin-12; low-density lipoprotein
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21155511

The formation of foam cells, which are macrophages that have engulfed oxidized low-density lipoprotein (OxLDL), constitutes the first stage in the development of atherosclerosis. Previously, we found that knocking down galectin-12, a negative regulator of lipolysis, leads to reduced secretion of monocyte chemoattractant protein-1 (MCP-1), a chemokine that plays an important role in atherosclerosis. This prompted us to study the role of galectin-12 in atherosclerosis. With that aim, we examined foam cell formation in Gal12 murine macrophages exposed to OxLDL and acetylated LDL (AcLDL). Then, we generated an LDL receptor and galectin-12 double knockout (DKO) mice and studied the effect of galectin-12 on macrophage function and atherosclerosis. Lastly, we evaluated the role of galectin-12 in human THP-1 macrophages using a doxycycline-inducible conditional knockdown system. Galectin-12 knockout significantly inhibited foam cell formation in murine macrophages through the downregulation of cluster of differentiation 36 ( ), and the upregulation of ATP Binding Cassette Subfamily A Member 1 ( ), ATP Binding Cassette Subfamily G Member 1 ( ), and scavenger receptor class B type 1 ( ). Consistent with this, galectin-12 knockdown inhibited foam cell formation in human macrophages. In addition, the ablation of galectin-12 promoted M2 macrophage polarization in human and murine macrophages as evidenced by the upregulation of the M2 marker genes, and and downregulation of the M1 cytokines, tumor necrosis factor α (TNF- α), interleukin-6 (IL-6), and MCP-1. Moreover, the ablation of galectin-12 decreased atherosclerosis formation in DKO mice. Based on these results, we propose galectin-12 as a potential therapeutic target for atherosclerosis.