Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases

Abstract

A large number of cardiovascular events are not prevented by current therapeutic regimens. In search for additional, innovative strategies, immune cells have been recognized as key players contributing to atherosclerotic plaque progression and destabilization. Particularly the role of innate immune cells is of major interest, following the recent paradigm shift that innate immunity, long considered to be incapable of learning, does exhibit immunological memory mediated via epigenetic reprogramming. Compelling evidence shows that atherosclerotic risk factors promote immune cell migration by pre-activation of circulating innate immune cells. Innate immune cell activation via metabolic and epigenetic reprogramming perpetuates a systemic low-grade inflammatory state in cardiovascular disease (CVD) that is also common in other chronic inflammatory disorders. This opens a new therapeutic area in which metabolic or epigenetic modulation of innate immune cells may result in decreased systemic chronic inflammation, alleviating CVD, and its co-morbidities.

Figure 1

Innate immune cell activation as a common pathway perpetuating the upheld inflammatory state in atherosclerosis and other chronic inflammatory disease states. Both non-modifiable (i.e. genome and gender) and modifiable (i.e. danger associated molecular patterns and pathogen-associated molecular patterns) risk factors can lead to the induction of epigenetic modifications in innate immune cells. Changes can occur in either haematopoietic stem cells or monocytes, leading to differentiation into reprogrammed monocytes or macrophages. This results in a hyper-responsive immune system, contributing to a chronic inflammatory disease state such as atherosclerotic cardiovascular diseases or chronic inflammatory diseases. Current therapies aim to lower risk factors, for example by lipid lowering. Future therapies might include additional epigenetic modulators, preventing and reversing the modification of innate immune cells, ideally by specifically targeting immune cells.

Figure 2

Monocyte reprogramming in atherosclerosis and chronic inflammatory diseases. Different chronic inflammatory disease states such as myocardial infarction, stroke, rheumatoid arthritis and gout as well as different atherosclerotic danger associated molecular patterns (DAMPs) such as low-density-lipoprotein, oxLDL, VLDL, and cholesterol crystals can trigger monocyte phenotype to change into a long-term activated monocyte. In the bone marrow, these pathogen-associated molecular patterns and danger associated molecular patterns alter the phenotype of the haematopoietic stem cells (HSCs) leading to the differentiation into a different monocyte phenotype and increased monocyte accumulation in the spleen and circulation. Furthermore, HSCs increasingly travel to the spleen leading to extramedullary haematopoiesis.