Research Themes Vascular damage Trained immunity and atherosclerosis
Cardiovascular diseases such as stroke and myocardial infarction are among the major causes of morbidity and mortality worldwide, and are the consequence of atherosclerosis. Atherosclerosis has long been recognized as a chronic low-grade inflammatory disorder of the arterial wall, but only last year it was reported that inhibiting systemic inflammation prevents cardiovascular disease. Cells of the innate immune system, including monocytes and macrophages, are key players in the development and progression of atherosclerosis. It has recently been established that, in contrast to traditional belief, these cells can also build a long-term immunological memory, which has been named ‘trained immunity’ (Science 2016).
Researchers of our theme who are members of the International Trained Immunity Consortium hypothesized that trained immunity contributes to the development of atherosclerosis and conducted various experiments spanning the entire range from molecule to population (Semin Immunol 2016). On the cellular level, we demonstrated that brief exposure of monocytes to various atherogenic stimuli, such as oxidized LDL or lipoprotein (a) triggers a long-term pro-atherogenic macrophage phenotype (Atheroscler Thromb Vasc Biol 2014; Circulation 2016). Multi-omics approaches revealed that this is mediated by profound metabolic and epigenetic reprogramming (Cell Metab 2016; Cell 2018). In animal models of atherosclerosis, a Western type diet induced prolonged innate immune activation which persisted after switching to a normal diet, due to epigenetic reprogramming of bone marrow progenitors (Cell 2018). On the patient level, we reported that monocytes from patients with established atherosclerosis or risk factors for atherosclerosis, have a trained immune phenotype (Circulation 2016, Atherosclerosis 2016). Finally, we have recently built a population-based cohort in which a functional genomics approach will allow us to study the determinants of chronic inflammation in relation to atherosclerosis.
This series of experiments has profoundly increased our understanding of the pathophysiology of atherosclerosis, provides a potential explanation for the link between infections and atherosclerosis (Circ Res 2018), and offers exciting opportunities to improve personalized cardiovascular risk prediction and personalized pharmacological treatment of cardiovascular diseases.