Abstract
Atherosclerosis is a chronic inflammatory disease and is the main cause of ischaemic heart disease, stroke, and other cardiovascular diseases. The development of atherosclerotic plaques incidence has been increasing significantly during the last few decades and is due to different factors, such as the increased consumption of high fat food, smoking and increased incidence of diabetes mellitus. This is currently a major burden on health systems, which require new therapeutic targets to address this challenge.The involvement of netrin-1 in inflammation and atherosclerosis has been studied during the last two decades. Different groups have established that netrin-1 plays a prominent role in these contexts and has different effects depending on where it is produced, and which cells are targeted by it. While endothelial-derived netrin-1 secreted into the circulation gives rise to a protective effect against atherosclerosis, macrophage-derived netrin-1 within the plaque has a pro-atherogenic effect, promoting the trapping and survivability of foam cells.
More recently, a truncated isoform of netrin-1 was found in the nuclei of different types of cancer cells. This form of netrin-1 has also been studied in endothelial cells, but so far, no relationship between the expression of truncated netrin-1 and macrophages has been established. The link between cytokine stimulation, macrophage phenotype and netrin-1 isoforms has until now been unclear. The work described in this thesis looked at the expression and function of netrin-1 on monocytes and different macrophage phenotypes.
Gene expression analysis revealed that macrophages express both full-length and truncated netrin-1. Classical activated is the macrophage phenotype that presents higher expression of netrin-1, and the expression of both isoforms is at least partially dependent on NF-κB activation pathway.
Netrin-1 inhibits monocyte migration by inhibiting chemokines’ chemoattractant effect. CCL2 and netrin-1 individually showed an attractant effect towards THP-1-derived macrophages, but the signals were inhibited when the two were combined. The apoptotic agent selected to study netrin-1 anti-apoptotic effect was not UNC5b-dependent and, therefore, limited our ability to acquire relevant data regarding this process.
Administration of exogenous netrin-1 to mice, increasing its systemic levels, showed an acute and chronic protective effect against inflammation. Mice treated with netrin-1 showed less macrophages within the tissue after the induction of local inflammation. Furthermore, increasing the netrin-1 systemic levels of mice prevented the enlargement of the aortic sinus and development of plaque after feeding them 60% HFD over a 6-week period.
This thesis provides relevant insights into the role of macrophage phenotypes in the expression of netrin-1 isoforms within atherosclerotic plaques, and how netrin-1 affects these immune cells. The findings highlight the significance of netrin-1 as a potential therapeutic target for treating not only cardiovascular disease but also other inflammatory conditions. Therefore, this research sheds light on the promising future of netrin-1 as a treatment option for a range of diseases.
| Date of Award | 1 Jan 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Albert Ferro (Supervisor) |