Abstract
Efforts to reverse the pathologic consequences of vulnerable plaques are often stymied by the complex treatment resistant pro-inflammatory environment within the plaque. This suggests that pro-atherogenic stimuli, such as LDL cholesterol and high fat diets may impart longer lived signals on (innate) immune cells that persist even after reversing the pro-atherogenic stimuli. Recently, a series of studies challenged the traditional immunological paradigm that innate immune cells cannot display memory characteristics. Epigenetic reprogramming in these myeloid cell subsets, after exposure to certain stimuli, has been shown to alter the expression of genes upon re-exposure. This phenomenon has been termed trained innate immunity or innate immune memory. The changed responses of ‘trained’ innate immune cells can confer nonspecific protection against secondary infections, suggesting that innate immune memory has likely evolved as an ancient mechanism to protect against pathogens. However, dysregulated processes of immunological imprinting mediated by trained innate immunity may also be detrimental under certain conditions as the resulting exaggerated immune responses could contribute to autoimmune and inflammatory diseases, such as atherosclerosis. Pro-atherogenic stimuli most likely cause epigenetic modifications that persist for prolonged time periods even after the initial stimulus has been removed. In this review we discuss the concept of trained innate immunity in the context of a hyperlipidemic environment and atherosclerosis. According to this idea the epigenome of myeloid (progenitor) cells is presumably modified for prolonged periods of time, which, in turn, could evoke a condition of continuous immune cell over-activation.
Highlights
Efforts to reverse the pathologic consequences of vulnerable plaques are often stymied by the complex treatment resistant pro-inflammatory environment within the plaque
In an in vitro model in human isolated monocytes, we found that trained innate immunity can be induced by modified LDL, but not by native LDL [36]
How immuno-metabolism is altered under conditions of hyperlipidemia and which metabolites potentially contribute to the establishment of a trained myeloid cell phenotype in atherosclerosis is still ill-defined
Summary
Macrophages are the most abundant subset of leukocytes. Blood leukocyte numbers were significantly increased as a result of increased circulating monocytes, along with the presence of a more activated splenic macrophage phenotype and increased plaque sizes In agreement with these data, Seijkens and colleagues [28] demonstrated in a competitive bone marrow transplantation study (transfer of normocholesterolemic bone marrow cells into either chow or high fat diet fed Ldlr−/− recipients) that a hypercholesterolemic BM microenvironment induced loss of HSC quiescence, characterized by increased expression of cyclin B1, C1 and D1, and skewed HSC development towards myeloid lineages, especially towards granulocytes and Ly6Chigh monocytes. HFD priming of bone marrow HSC remained even after transfer into normocholesterolemic mice and was associated with reduced H3K9/14 acetylation at the promoter of the retinoblastoma (RB) gene (involved in the control of excessive cell growth) These studies shed new light on the causality between hypercholesterolemia, altered epigenetic patterning in HSC and myeloid progenitors, and increased susceptibility to atherosclerosis. We postulate that long-term epigenetically reprogrammed myeloid precursor cells that are characterized by a hyper-inflammatory phenotype may contribute to a sustained disease progression [35] (Fig. 1)
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