Aernoud Fiolet

57 Viewing Atherosclerosis through a Crystal Lens with scavenger cells, they can be more rapidly cleared by resident macrophages that absorb them in an unregulated manner. Over time, resident macrophages become laden with lipid-rich lysosomes filled with free cholesterol, predisposing to the formation of CCs within them. 42, 43, 44 Further promoting the accumulation of free cholesterol within foamy macrophage is the degree of ACAT1 activity, which affects reverse cholesterol transport and the release of intracellular lipid. 45,46 As ox-LDL continues to accumulate within lysosomes, flat plate CCs form within themandmaybecome large enough to disrupt the lysosomal membrane. 47,48 leading to the release of cathepsin B,48 and CCs fragments directly into the cytosol. In this environment, fragments of flat plate CCs can be recognized as “foreign” by complosome, an intracellular cascade akin to complement, 49,50 , which together with cathepsin B may lead to the activation of the pyrin domain–containing 3 inflammasome 9, 51 and the expression of IL-1 β that enhances the influx of smooth muscle cells and fibrocytes, which eventually sequester foam cells. In addition, intracellular CCs may also activate caspase-8 leading to cellular dysfunction and ultimately apoptosis of these lipid laden macrophages. 52 Hence endothelial dysfunction induced by formation of CCs within the endothelial membrane acts in concert with on-going macrophage stimulation driven largely by free intracellular CCs to promote the formation and growth of atheroma. As new foam cells appear, they become sequestered in the fibrous matrix surrounding the plaque, and as they undergo apoptosis, their lipid contents may either be released into the plaque core, become sequestered in the surrounding fibrous capsule or released into the interstitial space. 52 CHOLESTEROL CRYSTALS IN THE INTERSTITIAL SPACE PROMOTE INFLAMMATORY INJURY Release of CCs into the interstitial space from fragmented lipid-rich CC-filled vesicles and apoptotic macrophages potentially marks an important stage in the atherosclerotic process that is largely affected by the rate of deposition and the size of the released CC fragments. Small fragments of flat plate CCs rapidly ingested by scavenger cells remain effectively sequestered from the interstitial space, however, once they begin to appear in the interstitial space faster than they can be cleared they may become “inflammatory targets” as exposed portions of their surface are recognized as