Stephen Malin

An excess of lipoproteins can result in their storage in inappropriate organs. This provokes the immune system and results in tissue damage and diseases, such as atherosclerosis and fatty liver. We want to discover how these diseases are initiated and how germinal centre formation can influence plaque formation in the aorta. We will look across multiple tissues to see how tissue identity imprints macrophage responses to dyslipidemia and how this can lead to inflammatory cross-talk between tissues. A special case will be the bone marrow, where lipoproteins are thought to interact with clonal haematopoiesis, perhaps through modifying niche macrophages. We outline how signalling through the Interleukin 7 receptor permits bone marrow B cells to take up lipoproteins to actually aid their growth, including in leukemia.To achieve this, we have created the first experimental system that allows a window into lipoprotein uptake and for monitoring the ‘Dyslipidemic insult’. We provide extensive preliminary results and outline our novel mouse models. Our approach uses multiple next-generation sequencing approaches together with classical pathology and immunology techniques.Our approach aims at disease prevention rather than cure, with an emphasis on atherosclerosis and fatty liver disease. We harness the power of immunotherapy to see if modifying immune responses can alleviate disease.

Background: Excessive inflammation causes and aggravates atherosclerosis and cardiovascular disease and therapeutic reduction of pro-inflammatory cytokines reduces adverse cardiovascular events in clinical trials. Considering accumulated data over recent decades, several observations suggest that neural signals regulate atherosclerosis development and cardiovascular risk. However, since atherosclerotic plaques lack direct innervation, neural regulation of inflammation in atherosclerosis was largely disregarded until now. We recently showed, together with partners in the Plaquefight consortium , that not only are atherosclerotic arteries innervated, but neuroimmune cardiovascular interfaces control atherosclerosis. Clinical translation of discoveries on neural regulation of disease pathogenesis has been hampered by the requirement of neurosurgical implantation of peripheral nerve stimulators. We collaborated to develop technology to enable precision non-invasive activation of peripheral nerves for experimental and clinical purposes. The work resulted in a novel, non-invasive, method for precision stimulation of peripheral nerves (patent pending). This approach is now in the process of approval for clinical trials. Objectives: In short, this program aims to detail how neural signals regulate atherosclerosis initiation and progression by studying unique animal models and patient samples, and initiate an clinical interventional study in patients with inflammatory microvascular angina. Work plan: A. Map the anatomy of arterial innervation in atherosclerosis by 1) visualizing the anatomy of atherosclerotic disease innervation 2) investigating neuro-immune interactions in adventitia and artery tertiary lymphoid organs B. Map the functional innervation of atherosclerotic arteries by 3) activating and de-activating neural signals in experimental atherosclerosis C. Investigate the safety and efficacy of non-invasive precision vagus nerve stimulation in microvascular angina by 4) investigating whether non-invasive vagus nerve stimulation in this patient group improves endothelial function and reduces inflammation. Significance: This research program has the potential to contribute with 1) tools for better understanding of the pathogenesis of atherosclerosis with identification of new therapeutic targets and 2) a novel approach to treatment of arterial inflammation and microvascular angina.

Heart attacks and strokes are the most common consequences of atherosclerosis, a chronic inflammatory disease affecting arteries. Atherosclerosis develops when cholesterol accumulates as plaque in the vessel wall, where it  triggers an inflammatory response. Recent clinical studies have shown that, in addition to lowering blood cholesterol levels, certain drugs that block inflammation can also help prevent atherosclerosis. However, these drugs have broad anti-inflammatory effects and are also associated with increased susceptibility to infections. Therefore, there is a great need to identify more specific drug targets that lack these side effects. B lymphocytes, a subset of white blood cells that are important to the immune response and the production of antibodies, are highly promising in this regard. The B cells in cardiovascular disease consortium (BCVD) will characterize these cells and their functions in human atherosclerosis and test the mechanisms by which they  can help to hinder disease in preclinical models. Based on these insights, the BCVD will develop novel innovative interventions that can ultimately be used as more precise anti-inflammatory therapies for the prevention of atherosclerotic cardiovascular disease.