Investigating the role of Galectin-9 in monocytes associated with atherosclerosis

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Krautter, Franziska (2022). Investigating the role of Galectin-9 in monocytes associated with atherosclerosis. University of Birmingham. Ph.D.

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Abstract

Cardiovascular disease is the number one cause of death worldwide. They are most often caused by atherosclerotic plaques, formed by lipid depositions in the vessel wall of major blood vessels which cause an inflammatory immune response. While it has been long accepted that the immune response is a driving factor in atherosclerotic plaque progression, no suitable therapeutics have been developed so far to successfully target inflammation and reduce the risk of cardiovascular events. Therefore the identification of new therapeutic targets involved in the progression of atherosclerosis and their mechanism of action is required in order to develop successful therapies.
Monocyte recruitment and migration into the vessel wall and their differentiation into macrophages, which release pro-inflammatory factors, and lipid-laden foam cells are driving forces of atherosclerosis. Many major proteins involved in the multistep adhesion cascade of leukocyte recruitment have been well characterised, however there are still gaps in knowledge.
Galectin-9 is a ß-galactoside binding protein and has been shown to have a wide range of functions. More recently, various studies have demonstrated its role in the modulation of leukocyte trafficking. However, its role in monocyte recruitment and migration remains elusive.
The aim of this study is to characterise the role of Galectin-9 in monocyte migration and atherosclerotic plaque progression.
The results show that Galectin-9 is expressed and released by human monocytes, macrophages and endothelial cells and its upregulation is induced by pro-inflammatory environments. Soluble Galectin-9 was demonstrated to induce human monocyte activation and the release of pro-inflammatory cytokines and chemokines by human monocyte derived macrophages. Additionally, it was observed that Galectin-9 upregulation by the endothelium is required for monocyte adhesion in vitro while PBMCs of peripheral arterial patients adhere to immobilised Galectin-9 with higher frequency compared to healthy young and aged controls. These inflammation-specific modes of function of Galectin-9 were confirmed in vivo: Galectin-9 induced monocyte and neutrophil migration into tissue during inflammation but not during homeostasis. Finally, the role of Galectin-9 in atherosclerotic plaque progression was demonstrated, since it was shown that ApoE-/- Gal-9-/- mice had a reduced plaque burden as well as a reduced macrophage and collagen content in aortic root plaques in a model of dietinduced atherosclerosis compared to ApoE-/- mice.
In conclusion this study demonstrates that inflammation-induced expression of Galectin-9 modulates atherosclerotic plaque progression in two ways: i) by facilitating monocyte recruitment and ii) through inducing a pro-inflammatory macrophage phenotype. These findings suggest that Galectin-9 is a novel therapeutic target in the prevention of atherosclerotic plaque progression.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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