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A new programme of research led by Professor Claudia Monaco and funded by the British Heart Foundation aims to unpick the inflammatory processes behind cardiovascular disease so that immune-targeted therapies may be developed in future.

Doctor taking patients heartbeat

Cardiovascular disease (CVD) kills about 480 people every day in the UK – it is the leading cause of death in men and second leading cause of death in women. Atherosclerosis underpins most cardiovascular disease by causing a build-up of lipid (fat) which narrows the arteries leading to heart attacks. Despite the availability of medications to limit cholesterol and blood pressure levels, and devices to widen arteries, atherosclerosis causes significant morbidity and mortality and better treatments are needed. The immune system has emerged as an integral part of our circulatory system and as such it pays a role in CVD. Thus, there is a growing interest in treating atherosclerosis with anti-inflammatory drugs, but by affecting the whole body they could leave patients more susceptible to infection. Creating anti-inflammatory therapies specifically targeted to the atherosclerotic plaque would minimise this side effect.

Our innate immune system has the helpful ability to trigger inflammation in response to infection and injury. In atherosclerosis, innate immune cells like macrophages become chronically activated by excess lipid and damage the artery walls. Toll-like receptors (TLRs) on the surface of macrophages are involved in this detrimental process, constantly recognising lipoproteins and triggering inflammation. Together this suggests that therapies to target macrophages and other cells in the atherosclerotic plaque could be powerful weapons to treat atherosclerosis. However, more knowledge about the molecular immunology of cardiovascular disease is needed to guide the design of future therapies.

A new programme grant, funded by the British Heart Foundation and led by Professor Claudia Monaco at the Kennedy Institute of Rheumatology in Oxford, aims to unpick the inflammatory processes of lipid-driven inflammation in atherosclerosis and to define the role of TLRs in more detail. This could lead to better therapies targeting the innate immune system.

Claudia’s lab has already found that specific TLRs play a role in atherosclerosis by contributing to the activation of lipid-associated macrophages or foam cells, the hallmark of atherosclerotic disease. They also showed that TLR signalling can be both protective or detrimental in atherosclerosis, a duality which could be caused by the specific cell signalling context or by small differences in the TLR molecules. TLR2 promotes atherosclerosis by driving the formation of pro-inflammatory lipid-associated macrophages, a subset of macrophages with cerebrovascular symptoms. TLR3 and TLR7, in contrast, may protect against atherosclerosis.

Their research aims to take these findings to the next level. Claudia and her collaborators will study the single-cell datasets that they have generated to identify the specific context of TLR molecules, cells, and molecular pathways responsible for promoting and protecting against inflammation in atherosclerosis. In doing so, they aim to discover new therapeutic targets which could lead to safe and effective therapies based on targeting innate immune cells in the artery wall.

‘Despite medical advances, cardiovascular disease is still the biggest killer’ said Professor Claudia Monaco. ‘We know that the immune system contributes to atherogenesis but our understanding of the immunology of the human plaque is incomplete and the molecular determinants of lipid-driven inflammation are still vague. Our discovery that the activation of lipid-associated macrophages in the human plaque is dependent on innate immune receptors. TLRs offer new avenues to stop atherosclerosis and reduce the burden of cardiovascular disease.’

In addition to Claudia, research on the programme grant will be carried out by Chris O'Callaghan, Stephen Sansom, Chiara Giannarelli, Kim Midwood, Jelena Bezbradica Mirkovic, Luke O'Neill, Regent Lee, Mads Gyrd-Hansen, Benedikt M. Kessler, Christophe Lamaze, Isabel Goncalves, and Robin Choudhury.

The researchers would like to thank the British Heart Foundation for their generous funding.