Abstract With innate immunity at the core of the pathophysiology of atherosclerosis, the discovery of new mechanisms of immune cell activation can potentially identify novel pharmacological targets to prevent or treat cardiovascular disease (CVD). One of these mechanisms is trained immunity (TRIM), defined as a recallable long-term hyperinflammatory innate immune phenotype supported by changes of metabolic and epigenetic intracellular processes. TRIM can be induced in mature innate immune cells in tissues, including monocytes/macrophages, and natural killer cells, but also in non-immune cells such as endothelial and epithelial cells (peripheral TRIM). Bone marrow haematopoietic stem and progenitor cells can also be trained (central TRIM), which explains the long-term presence of trained cells, such as monocytes and neutrophils, in the circulation. Recent experimental studies in mice revealed that central TRIM can be induced by traditional CVD risk factors (including diet-induced obesity or intermittent high-fat diet, hyperglycaemia, and hypertension), inflammatory co-morbidities (such as periodontitis and arthritis), unhealthy life-style factors (psychosocial stress and sleep disturbance), and by mechanisms activated by experimental myocardial infarction and stroke. This leads to the long-term presence of hyperinflammatory monocytes and neutrophils that can subsequently accelerate atherosclerosis development. A key mechanism that drives the development of central TRIM in many of these conditions is IL-1β signalling in the bone marrow. In addition, rewiring of cellular metabolism (e.g. activation of glycolysis and glutaminolysis) and changes in histone methylation, acetylation, and lactylation mediate the development of central and peripheral TRIM. We propose that prevention of TRIM by pharmacological targeting of these pathways in myeloid cells represents a new avenue for the prevention and treatment of cardiovascular events.
Riksen et al. (Fri,) studied this question.