Final Report Summary - IM TARGETING CVD (Accelerated Atherosclerosis in Patients with Immune Mediated Disorders as a Model to Investigate the Link between Inflammation and Cardiovascular Disease: From Basic Mechanisms to Clinical Application)
Background and rationale: Atherosclerosis is a chronic inflammatory disease of the arterial wall with (auto)immune component, initiated in response to modified (phospho)lipids. Despite important advances in our understanding of the inflammatory response in atherosclerosis, the critical pathways responsible for the breakdown of immune tolerance to lipoproteins and other self-antigens remain largely unknown. An important feature of ruptured/thrombosed atherosclerotic lesions is the accumulation of apoptotic, and secondary necrotic lipid-laden macrophages and smooth muscle cells due to defective efferocytosis (clearance of apoptotic cells). This leads to the formation of a large ‘necrotic’ lipid core, associated with enhanced vascular inflammation. Interestingly, defective efferocytosis has been associated with the development of autoimmunity, and patients with systemic lupus erythematosus who show increased accumulation of apoptotic material are at very high risk of accelerated atherosclerosis and myocardial infarction. We hypothesized that accumulation of apoptotic/secondary necrotic cells due to defective efferocytosis, together with modified lipids, activate critical immuno-inflammatory pathways in macrophages and B cells, and break immune tolerance in atherosclerosis and post-myocardial infarction. We also proposed that interactions between macrophages and B cells are essential for the perpetuation of the pathogenic immuno-inflammatory response in cardiovascular disease.
Project outcomes: We have identified new roles for necrotic cell signalling (through CLEC4E and CLEC9A) in high fat diet-induced atherosclerosis and the response to ischemic injury. We have defined new roles for MFGE8 (involved in apoptotic cell clearance) in the regulation of NLRP3 inflammasome. We have also shown that a microtubule regulated kinase, MARK4, is essential for NLRP3 activation through regulation of its subcellular positioning to the mitochondria and the MTOC. We have identified major roles for distinct B cell subsets in atherosclerosis and the response to ischemic myocardial injury. The results were published in high impact journals, including Nature Medicine (2), Nature Communications (2), Journal of Clinical Investigation, Cell Metabolism, Circulation (2), Circulation Research, Journal of teh American College of Cardiology, Nature Reviews Cardiology, etc. We have also obtained an ERC PoC grant to translate our findings to the clinical setting. We are currently testing the safety and biological efficacy of B cell depletion at the acute phase of ST-elevation of myocardial infarction.
Project outcomes: We have identified new roles for necrotic cell signalling (through CLEC4E and CLEC9A) in high fat diet-induced atherosclerosis and the response to ischemic injury. We have defined new roles for MFGE8 (involved in apoptotic cell clearance) in the regulation of NLRP3 inflammasome. We have also shown that a microtubule regulated kinase, MARK4, is essential for NLRP3 activation through regulation of its subcellular positioning to the mitochondria and the MTOC. We have identified major roles for distinct B cell subsets in atherosclerosis and the response to ischemic myocardial injury. The results were published in high impact journals, including Nature Medicine (2), Nature Communications (2), Journal of Clinical Investigation, Cell Metabolism, Circulation (2), Circulation Research, Journal of teh American College of Cardiology, Nature Reviews Cardiology, etc. We have also obtained an ERC PoC grant to translate our findings to the clinical setting. We are currently testing the safety and biological efficacy of B cell depletion at the acute phase of ST-elevation of myocardial infarction.