Aernoud Fiolet

16 Chapter 1 adventitia. 24,25 This classic dichotomous subdivision of macrophage phenotypes is probably too simplified, as a more diverse continuum of cell type differentiation may be found in the plaque. 26 The CD36 receptor is the most notable scavenger receptor for binding oxidised LDL in the intima. Lipid accumulation in the macrophage does not suppress CD36 expression, making room for unrestricted lipid accumulation. 27 Engulfing the lipids, large numbers of macrophages develop lipid droplets, giving them a foamy appearance (“foam cells”). 28 The large number of macrophages filled with lipid droplets finally perish and release their intracellular contents. This occurs mainly due to apoptosis and secondary necrosis from the toxicity of the oxidised LDL and hypoxia. Without effective efferocytosis—the immunological phenomenon where apoptotic cells are cleared out—large pools with cellular debris form. 29–31 Summarizing, the macrophage thus plays a distinct role in the initiation and morphological changes of atherosclerotic plaque. 32 The learned innate immune system Classically, the innate immune system is said to operatewithout an “immunological memory.” However, for longer, observations have suggested the existence of “trained innate immunity.” 33 After genetically eliminating the adaptive immune system of mice that were administered a vaccination for tuberculosis and introduced to diverse second inflammatory stimuli at a later stage, all demonstrated augmented monocyte production. This proves that the innate immune system is able to increase its response after second similar and different threats, without the involvement of the adaptive immune system. 34 The change to a pro-inflammatory monocyte occurs via DNA methylation or “epigenetic modification.” Not only exogenous pathogens, such as bacteria, can induce this mechanism of “trained innate immunity”, but endogenous antigens may also introduce this epigenetic reprogramming of the monocyte. This indicates the importance of “trained innate immunity,” in atherosclerosis as well. 35 Indeed, oxidised LDL acting as the first stimulus to such monocytes produces highly pro-atherogenic monocytes. 36 The controversial association between traces of microorganisms (such as Chlamydia pneumoniae or viruses) in atherosclerotic plaques, and their role in the development of these plaques may also relate to this mechanism. 35