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Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization
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 mon...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432701/ https://www.ncbi.nlm.nih.gov/pubmed/32752134 http://dx.doi.org/10.3390/ijms21155511 |
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author | Lin, En-Shyh Hsu, Yu-An Chang, Ching-Yao Lin, Hui-Ju Chen, Chih Sheng Wan, Lei |
author_facet | Lin, En-Shyh Hsu, Yu-An Chang, Ching-Yao Lin, Hui-Ju Chen, Chih Sheng Wan, Lei |
author_sort | Lin, En-Shyh |
collection | PubMed |
description | 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 (CD36), and the upregulation of ATP Binding Cassette Subfamily A Member 1 (ABCA1), ATP Binding Cassette Subfamily G Member 1 (ABCG1), and scavenger receptor class B type 1 (SRB1). 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, CD206 and CD163, 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. |
format | Online Article Text |
id | pubmed-7432701 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-74327012020-08-27 Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization Lin, En-Shyh Hsu, Yu-An Chang, Ching-Yao Lin, Hui-Ju Chen, Chih Sheng Wan, Lei Int J Mol Sci Article 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 (CD36), and the upregulation of ATP Binding Cassette Subfamily A Member 1 (ABCA1), ATP Binding Cassette Subfamily G Member 1 (ABCG1), and scavenger receptor class B type 1 (SRB1). 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, CD206 and CD163, 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. MDPI 2020-07-31 /pmc/articles/PMC7432701/ /pubmed/32752134 http://dx.doi.org/10.3390/ijms21155511 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lin, En-Shyh Hsu, Yu-An Chang, Ching-Yao Lin, Hui-Ju Chen, Chih Sheng Wan, Lei Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization |
title | Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization |
title_full | Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization |
title_fullStr | Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization |
title_full_unstemmed | Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization |
title_short | Ablation of Galectin-12 Inhibits Atherosclerosis through Enhancement of M2 Macrophage Polarization |
title_sort | ablation of galectin-12 inhibits atherosclerosis through enhancement of m2 macrophage polarization |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432701/ https://www.ncbi.nlm.nih.gov/pubmed/32752134 http://dx.doi.org/10.3390/ijms21155511 |
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