Monaco Group | Cardiovascular Inflammation
Cardiovascular disease (CVD) is the biggest killer world-wide in the general population and affects disproportionately patients with chronic inflammatory diseases. Thick-walled large and medium sized arteries, where atherosclerosis – the main cause of CVD – occurs, have their own immune cell complement embedded within. As atherosclerotic “plaques” develop, immune cells have a non-redundant role in causing CVD. The vascular wall immune cell complement is heterogeneous and, contrary to earlier expectations, it performs both homeostatic and pathogenic functions. Discrimination between pathogenic and reparative cell states is crucial to design safe and selective diagnostic and therapeutic approaches targeting immunity in cardiovascular disease.
The Cardiovascular Inflammation Laboratory (CVIL) is focused on the discovery of the cellular building blocks of atherosclerotic plaques. We generate atlases of human and murine atherosclerosis as part of several multicentre projects bringing together cardiologists, vascular surgeons, immunologists and vascular biologists. Applying and tailoring single cell technologies to arteries we have enumerated and characterized novel immune subsets within the arterial wall in health and disease, their distribution, and their dynamics during atherogenesis. Combining single cell biology platforms such as 10x genomics and mass cytometry with mutant mice we assign specific functions to discrete vascular immune cell subsets. We are currently using these insights to decipher the intricate regulation of cell subset function and education in the atherosclerotic microenvironment with a focus on innate immunity.
We are actively recruiting. PhD studentships and postdoctoral positions are available. Email firstname.lastname@example.org to express interest.
Available studentship projects
1. How vascular resident macrophages fend off atherosclerosis?
We have uncovered underappreciated myeloid cell dynamics in atherogenesis that feature consistently across models and intervention. One key feature is the rarefaction of adventitial tissue resident macrophages during atherogenesis. We discovered the first athero-protective subset of resident vascular macrophages and the CLEC4A2 C-type lectin pathway that defines and maintains their pool by acting as a switch favouring CSF1 over CSF2-drive developmental fates (Nat Comm 2022). Understanding of the transcription factors and receptors that underpin their protective abilities will provide novel mechanisms to enhance arterial homeostasis and prevent its disruption. Finally, using single cell technologies in human plaques we are translating the murine myeloid phenotypes to human atherosclerotic and healthy vascular tissues.
2. What are the drivers of pathogenic intimal macrophage subsets?
The existence and pro-atherogenic role of intimal CD11c+ myeloid cells was known in murine atherosclerosis. However, their master regulators and their role in humans was unknown. We showed that downstream of TLR signalling, the transcription factor IRF5 drives intimal macrophages towards a pro-inflammatory CD11c+ state and away from a CD61+ efferocytic state, leading to an impairment of the uptake of apoptotic cells and the formation of a large apoptotic core (Circulation 2017). Via a multi-omics (CyTOF and bulk sequencing) and a reverse translational approach, we showed that that arterial intimal CD11c+ macrophages cluster at the shoulder of the human plaque, are dependent on interferon regulatory factor 5 and are involved in plaque rupture (EHJ 2022). We are currently decoding the cellular and intracellular mechanism of activation of inflammatory arterial intimal macrophages via mapping of ligand-receptor interactions in the atheroma cell communities via single cell transcriptomics and spatial atherosclerotic tissue analysis.
- BHF-funded Oxford Centre of Excellence (BHF CRE)
- Novo Nordisk Foundation Immunometabolism Programme participants (MERIAD).
- Esther Lutgens, Mayo Clinic, USA and other colleagues in the 2022-funded Leducq Transatlantic network Checkpoint Athero