Fernando-Sayers, Jacob;
(2022)
Role of Neuropilins in regulating macrophage function and the development of atherosclerotic plaques in the mouse.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Background. Ischaemic heart disease is the leading cause of mortality worldwide and atherosclerosis is the underlying pathology in most cases. Macrophages are heterogenous inflammatory cells that play a central role in the development of atherosclerosis. As such, they are an attractive therapeutic target in preventing atherosclerotic plaque development. Neuropilins (NRPs) are cell- surface glycoproteins that were initially found to be essential for cardiovascular development and axonal guidance. Neuropilins are now known to be multi- functional co-receptors, and are expressed by macrophages. To build upon our current understanding of the molecular mechanisms underpinning macrophage involvement in atherosclerosis, I characterised the role of NRPs in modulating macrophage function and atherosclerotic plaque development. Methods. I generated mouse lines with myeloid-specific knockout (KO) of Nrp1 or Nrp2, on a pro-atherogenic background (Nrp1-KOMac,Apoe-/-,EYFP and Nrp2- KOMac,Apoe-/-,EYFP). These mice were fed high-fat diet (HFD) for 16 weeks before their aortas were removed, and plaques were characterised. This study was complemented by polarisation experiments, functional assays and transcriptome analysis, using Nrp1-KO or Nrp2-KO macrophages. Results. HFD-induced plaque development was significantly attenuated in both Nrp1-KOMac,Apoe-/-,EYFP and Nrp2-KOMac,Apoe-/-,EYFP mice, however the composition of their plaques differed. Plaques from Nrp2-KOMac,Apoe-/-,EYFP mice had features of increased stability, whereas plaques from Nrp1-KOMac,Apoe-/-,EYFP mice had features of reduced stability. Transcriptome analysis revealed that interferon signalling, chemotaxis and cholesterol efflux pathways were downregulated in Nrp1-KO macrophages, whereas NFκB signalling and chemotaxis pathways were downregulated in Nrp2-KO macrophages. Furthermore, M1 macrophage polarisation was enhanced in Nrp1-KO, but inhibited in Nrp2-KO, macrophages and MCP-1-guided migration was impeded in both Nrp1-KO and Nrp2-KO macrophages. Conclusions. I have demonstrated that macrophage-derived NRPs are pro- atherogenic, which likely results from their ability to positively regulate pro- inflammatory pathways and macrophage migration. Targeting NRPs expressed on the surface of macrophages could therefore offer a novel therapeutic approach for reducing the disease burden associated with atherosclerosis.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Role of Neuropilins in regulating macrophage function and the development of atherosclerotic plaques in the mouse |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10142050 |
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