The role of vascular macrophages in cardiovascular health and disease

PROJECT OVERVIEW

Macrophages have a key role in health and disease, by supporting organ function and immune responses to damage and disease. In homeostasis, ontogeny and organ-specific signals influence the phenotype and function of macrophages by activation of specific transcription factors. Disruption of homeostasis due to inflammation, infection or disease results in a drastically altered tissue micro-environment with the influx of newly recruited monocytes and macrophages and inflammatory substances. The macrophage phenotype under non-homeostatic conditions is reshaped by integration of maturation, polarisation, activation and deactivation events via growth factors and cytokines, inducing a myriad of activation states.

Cardiovascular disease is an exemplar of how mononuclear phagocytes are directly implicated in health and disease pathogenesis (1). The study of the functions of vascular macrophages has so far been neglected and is a current area of exciting discovery.

We have recently applied single cell technologies to the identification of homeostatic vascular macrophages (2), and how modulating macrophage behaviour affects atherogenesis and plaque complications (3). We have also shown how lymphatic vessels interactions with cardiac macrophage affect heart regeneration (4-5), and that cardiac and vascular macrophages share similar phenotypes (2,4-5).

This project aims to investigate the biology and molecular regulation of cardiovascular macrophages in health and disease. State-of-the-art single cell technologies will be combined with genetic deletion, fate mapping, and functional studies to define the role of cardiovascular macrophages and their interactions with neighbouring cells in health, atherogenesis and myocardial infarction.

This project will take advantage of the state-of-the-art facilities and equipment of the two host Institutes - KIR and IDRM, conveniently located in close proximity in the Old Road Campus, to ascertain the niche and cell-cell communications that condition cardiovascular macrophages phenotype and their tissue adaptations during cardiovascular disease.

KEYWORDS (5 WORDS)

Cardiovascular

Macrophages

Inflammation

Homeostasis

Immunity

TRAINING OPPORTUNITIES

The student will benefit from the availability of in-house state-of-the-art single cell technologies including transcriptomics and proteomics approaches using dissociative methods but also spatial methodologies including spatial transcriptomics and CyTOF Hyperion for tissue imaging in human and mouse models of atherogenesis and myocardial infarction. Moreover,  training in advanced bioimaging, of macrophages in the local injury environment will take advantage of the Oxford-Zeiss Centre of Excellence and state-of-the-art microscopy located within the two host Institutes- KIR and IDRM.

KEY PUBLICATIONS (5 maximum)

1.         Engelen SE, Robinson AJB, Zurke YX, Monaco C. Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed? Nat Rev Cardiol. 2022 Jan 31:1-21. doi: 10.1038/s41569-021-00668-4. PMID: 35102320

2.         Park I, Goddard ME, Cole JE, Zanin N, Lyytikäinen LP, Lehtimäki T, Andreakos E, Feldmann M, Udalova I, Drozdov I, Monaco C. C-type lectin receptor CLEC4A2 promotes tissue adaptation of macrophages and protects against atherosclerosis. Nat Commun. 2022 Jan 11;13(1):215. doi: 10.1038/s41467-021-27862-9. PMID: 35017526

3.         Edsfeldt A, Swart M, Singh P, Dib L, Sun J, Cole JE, Park I, Al-Sharify D, Persson A, Nitulescu M, Das Neves Borges P, Kassiteridi C, Goddard ME, Lee R, Volkov P, Orho-Melander M, Maegdefessel L, Nilsson J, Udalova I, Goncalves I, Monaco C. IRF5-dependent CD11c+ macrophages contribute to the formation of rupture prone atherosclerotic plaques. Eur Heart J. 2022 Feb 9:ehab920. doi: 10.1093/eurheartj/ehab920. PMID: 35139193.

4.         Joaquim Miguel Vieira, Sophie Norman, Cristina Villa Del Campo, Thomas J Cahill, Damien N Barnette, Mala Gunadasa-Rohling, Louise A Johnson, David R Greaves, Carolyn A Carr, David G Jackson, Paul R Riley.  The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. J Clin Invest 2018 Aug 1;128(8):3402-3412.PMID: 29985167

5.         Linda Klotz, Sophie Norman, Joaquim Miguel Vieira, Megan Masters, Mala Rohling, Karina N Dub√©, Sveva Bollini, Fumio Matsuzaki, Carolyn A Carr, Paul R Riley. Cardiac lymphatics are heterogeneous in origin and respond to injury. Nature 2015 Jun 4;522(7554):62-7. PMID: 25992544

THEMES (4 key themes)

Immunology, Cardiovascular Science

CONTACT INFORMATION OF ALL SUPERVISORS

Claudia Monaco, Professor Cardiovascular Inflammation, Kennedy Institute, claudia.monaco@kennedy.ox.ac.uk

Paul Riley, Director, Institute of Developmental and Regenerative Medicine, paul.riley@idrm.ox.ac.uk

Inhye Park, Post-doctoral fellow, Kennedy Institute, inhye.park@kennedy.ox.ac.uk