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Abstract
Background and aims: Atherosclerosis is widely accepted to be an inflammatory disease driven by lipid accumulation and leukocyte recruitment. More recently, galectins, a family of β-galactoside binding proteins, have been shown to play a role in leukocyte recruitment among other immunomodulatory functions. Galectin (Gal) −9, a tandem repeat type galectin expressed by the endothelium in inflammatory environments, has been proposed to promote leukocyte recruitment. However, the role of Gal-9 in the context of monocyte recruitment remains elusive.
Methods and Results: Here, we characterise the immunomodulatory role of Gal-9 in context of atherosclerosis. We show that ApoE−/−Gal-9−/− mice have a significantly reduced aortic plaque burden compared to their ApoE−/− littermate controls after 12 weeks of high fat diet. RNA sequencing data from two independent studies reveal Lgals9 expression in leukocyte clusters isolated from murine atherosclerotic plaques. Additionally, soluble Gal-9 protein induces monocyte activation and a pro-inflammatory phenotype in macrophages. Furthermore, we show that immobilised recombinant Gal-9 acts as capture and adhesion molecule for CD14+ monocytes in a β2-integrin and glycan dependent manner, while adhesion of monocytes to stimulated endothelium is reduced when Gal-9 is knocked down. Gal-9 also facilitates enhanced recruitment of leukocytes from peripheral arterial disease (PAD) patients compared to healthy young and aged controls. We further characterise the endothelium as source of circulating Gal-9, which is increased in plasma of PAD patients compared to healthy controls.
Conclusions: These results highlight a pathological role for Gal-9 as promoter of monocyte recruitment and atherosclerotic plaque progression, making it a novel target in the prevention of plaque formation and progression.
Methods and Results: Here, we characterise the immunomodulatory role of Gal-9 in context of atherosclerosis. We show that ApoE−/−Gal-9−/− mice have a significantly reduced aortic plaque burden compared to their ApoE−/− littermate controls after 12 weeks of high fat diet. RNA sequencing data from two independent studies reveal Lgals9 expression in leukocyte clusters isolated from murine atherosclerotic plaques. Additionally, soluble Gal-9 protein induces monocyte activation and a pro-inflammatory phenotype in macrophages. Furthermore, we show that immobilised recombinant Gal-9 acts as capture and adhesion molecule for CD14+ monocytes in a β2-integrin and glycan dependent manner, while adhesion of monocytes to stimulated endothelium is reduced when Gal-9 is knocked down. Gal-9 also facilitates enhanced recruitment of leukocytes from peripheral arterial disease (PAD) patients compared to healthy young and aged controls. We further characterise the endothelium as source of circulating Gal-9, which is increased in plasma of PAD patients compared to healthy controls.
Conclusions: These results highlight a pathological role for Gal-9 as promoter of monocyte recruitment and atherosclerotic plaque progression, making it a novel target in the prevention of plaque formation and progression.
Original language | English |
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Pages (from-to) | 57-68 |
Number of pages | 12 |
Journal | Atherosclerosis |
Volume | 363 |
Early online date | 19 Nov 2022 |
DOIs | |
Publication status | Published - 1 Dec 2022 |
Keywords
- Macrophages
- Galectin-9
- Atherosclerosis
- Monocytes
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Dive into the research topics of 'Galectin-9: a novel promoter of atherosclerosis progression'. Together they form a unique fingerprint.Projects
- 3 Finished
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Endocytosis and receptor trafficking in human megakaryocytes - Sub-project of 21502
Dalby, A.
1/11/20 → 31/07/22
Project: Research
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Investigating the role of galectins in chronic inflammation associated with atherosclerosis
THE ACADEMY OF MEDICAL SCIENCES
4/06/18 → 3/06/20
Project: Research