Aernoud Fiolet

58 Chapter 2 “foreign” by complement factors. Activation of complement factor C3a stimulates endothelium to produce selectins, which promote the ingress of circulating leukocytes, and activation of factor C5a and C5b-9 stimulates macrophages to produce inflammasome. 32,53, 54, 55 In addition, fragments of flat plate CCs can act as “inflammatory triggers” as they can be recognized by and act as endogenous ligands for human macrophage-inducible C-type lectin (hMincle) receptors on the surface of macrophages and scavenger cells. 56 Finally, larger flat plate CCs fragments in the interstitial space that cannot be fully ingested by scavenger cells may predispose to “frustrated phagocytosis”, a process in which intracellular lysosomal contents are released directly into the interstitial space leading to an indolent and at times a more intense immune response that can be associatedwith the expression of neutrophil extracellular traps (NETs) that leads to necroptosis,which further enhances the risk of inflammatory injury. 4,57,58 Each of these proinflammatory effects of extracellular flat plate CCs can be augmented by regional hypoxia, and the release of adenosine triphosphate and other toxins from apoptotic cells that can activate inflammasome via the purinergic 2X7 receptor (P2X7R) and lead to the formation of reactive oxygen species. 59,60 Hence, flat plate CCs that appear and persist in the interstitial space promote and augment inflammation by several mechanisms independent of the effects of intracellular CCs and therefore contribute to progressive fibrosis, dystrophic calcification, and neovascularization of the vessel wall. Clinical studies highlight that these processes also contribute to acute vascular injury, as evidence by the increased expression of IL-1 β ,61,62 the release of metalloproteinases-9 (MMP-9) and TNF- α , 63 and the expression of neutrophilic NETs found in aspirated blood from infarct-related arteries 64 in the setting of acute coronary syndromes. RAPID TRANSITION OF METASTABLE CHOLESTEROL CRYSTALS WITHIN THE PLAQUE CORE CAN PROMOTE TRAUMATIC INJURY Inflammatory injury alone does not explain every instance of plaque disruption. Rather, the final coup de grace leading to plaque rupture can result from the ability of CCs to cause traumatic injury. Small needle shaped helical forms of (metastable) intracellular and extracellular CCs have been demonstrated to directly damage cellular membranes of scavenger cells causing release of their content into the tissue space, however, these effects are likely small compared with the effect of changes in structure of CCs in the plaque core. 7,48