Stress‐induced trained immunity—A key mechanism linking psychosocial stress, atherosclerosis, and cardiovascular disease

Although chronic psychosocial stress is a well-established independent risk factor for cardiovascular disease (CVD), the underlying mechanisms linking stress to CVD remain incompletely understood. Here, we review clinical and preclinical research documenting how stress can activate innate immune cells. Based on these findings, we propose that trained innate immunity is one possible mechanism responsible for the lasting effects of stress on the innate immune system, and hence contributes to the association between stress and CVD. Trained immunity is defined as a persistent hyperinflammatory phenotype in innate immune cells, mediated by metabolic and epigenetic reprogramming of the bone marrow myeloid progenitor cells. As we describe herein, accumulating experimental evidence shows that chronic psychosocial stress can induce a maladaptive trained immunity program that accelerates atherosclerosis. By advancing our understanding of stress-induced trained immunity, we will move one step closer to designing new therapeutic, behavioral, and lifestyle strategies to counter maladaptive immune activation and reduce risk for CVD, one of the greatest causes of morbidity and mortality worldwide.