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Published on: October 17, 2017
Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis
Yongting Luo1, Hongxia Duan1, Yining Qian2
1Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Insights
Adhesion receptor CD146 traps cholesterol-filled foam cells within artery walls, driving atherosclerosis. Blocking CD146 promotes foam cell exit, reducing plaque complexity and offering a new therapeutic target.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cell Biology
Background:
- Atherosclerosis development is fueled by cholesterol-engorged macrophages (foam cells) persisting in artery walls.
- Mechanisms regulating foam cell formation and their emigration from plaques are not fully understood.
Purpose of the Study:
- To investigate the role of adhesion receptor CD146 in foam cell formation and retention within atherosclerotic plaques.
- To explore CD146 as a potential therapeutic target for atherosclerosis.
Main Methods:
- Investigated CD146 expression in human and mouse atheroma.
- Examined CD146's effect on macrophage lipid uptake via scavenger receptor CD36.
- Assessed macrophage migration in response to chemokines CCL19 and CCL21.
- Utilized CD146 knockout and antibody blockade in high-fat diet-fed ApoE-/- mice models.
Main Results:
- CD146 is upregulated by oxidized low-density lipoprotein (oxLDL) and triggers macrophage activation by promoting CD36 internalization.
- Macrophage migration towards CCL19 and CCL21 is reduced by oxLDL but restored upon CD146 blockade.
- Genetic deletion or antibody targeting of CD146 significantly reduced plaque complexity by promoting foam cell emigration.
Conclusions:
- CD146 acts as a novel retention signal, trapping macrophages within the artery wall and exacerbating atherosclerosis.
- Targeting CD146 presents a promising therapeutic strategy for treating atherosclerosis.
Abstract:
The persistence of cholesterol-engorged macrophages (foam cells) in the artery wall fuels the development of atherosclerosis. However, the mechanism that regulates the formation of macrophage foam cells and impedes their emigration out of inflamed plaques is still elusive. Here, we report that adhesion receptor CD146 controls the formation of macrophage foam cells and their retention within the plaque during atherosclerosis exacerbation. CD146 is expressed on the macrophages in human and mouse atheroma and can be upregulated by oxidized low-density lipoprotein (oxLDL). CD146 triggers macrophage activation by driving the internalization of scavenger receptor CD36 during lipid uptake. In response to oxLDL, macrophages show reduced migratory capacity toward chemokines CCL19 and CCL21; this capacity can be restored by blocking CD146. Genetic deletion of macrophagic CD146 or targeting of CD146 with an antibody result in much less complex plaques in high-fat diet-fed ApoE-/- mice by causing lipid-loaded macrophages to leave plaques. Collectively, our findings identify CD146 as a novel retention signal that traps macrophages within the artery wall, and a promising therapeutic target in atherosclerosis treatment.
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