Aernoud Fiolet

54 Chapter 2 the size of the free cholesterol pool, the amount of phospholipid, the extent of hydration of the cholesterol molecules, the presence of excess calcium, regional pH, and ambient temperature. 11, 12, 13, 14, 15 Figure 1. Effects of flat plate cholesterol crystals in atherosclerotic plaques. In macrophages, flat plate CCs within lysosomes may be large enough to disrupt lysosomal membranes leading to the release of cathepsin B (Green Dots), and CC fragments directly into the cytosol. In the cytosol, the surface of flat plate CCs can be recognized by complosome (Blue Dot) that together with cathepsin B may trigger NLRP3 inflammasome. In addition, flat plate CCs in the cytosol may trigger caspase 8 (Red Dot) initiating apoptosis. In the interstitial space, the surface of flat plate CCs released from lipid-rich vesicles and apoptotic macrophages promote inflammatory injury as they are recognized by hMincle receptors on macrophages, and by complement factor C5a and C5b-9 that augments inflammasome expression, and C3a, which promotes endothelial expression of selectins, which augments the chemoattractant effect of IL-1 β and enhances the ingress of circulating leukocytes. In addition, large flat plate CCs that cannot be ingested by scavenger cells can induce frustrated phagocytosis leading to persistent inflammation. In the plaque core, release of cellular debris from apoptotic leukocytes can abruptly change the physiochemical environment accelerating the transition of metastable CCs into massive flat plate CCs that can cause plaque expansion, hemorrahge from vasavasorum and direct trauma that can lead to plaque rupture or trigger inflammation as small CC fragments become exposed to the interstitial space. CCs, cholesterol crystals; COMP, complosome; hMincle, human macrophage–inducible C-type lectin; IL-1 β , interleukin 1 β . Formation of CCs in atherosclerotic plaque likely follows the same transitional sequence seen in vitro in bile fluid. In that setting, CCs form and transition through a series of metastable crystalline structures, first appearing as long thin flexible flat ribbons that grow into filaments, which then turn on their axis to form α -helices, which then form into narrow tube-like structures. Fortuitously, the flexible filamentous nature of metastable CCs is an efficient means of stacking large numbers of free cholesterol molecules into a confined space. As these metastable