Aernoud Fiolet

76 Chapter 3 CRYSTAL-INDUCED INFLAMMATION IN ATHEROSCLEROSIS Many irritative stimuli (eg, hypertension, dyslipidemia, smoking, metabolic syndrome) lead to vascular endothelial dysfunction and intimal accumulation of LDL particles, forming asymmetric atherosclerotic plaques in the arterial wall, covered by a fibrous cap. 12,13 The deposition of lipid-laden macrophages within the arterial wall is followed by an inflammatory response to the formation of free crystalline cholesterol within the interstitial space. Cholesterol can form large crystalline structures within plaque, leading to volume expansion; crystals that migrate to the surface of the plaquemayperforate the cap of the plaque. Cholesterol crystal embolization may cause distal ischemia and tissue inflammation. 14,15 In addition, cholesterol crystals can incite a direct inflammatory response, consisting of interleukin, complement, and neutrophil action. Macrophages respond to crystals by inducing a NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome–mediated interleukin-1 beta release, as seen in other crystalline pathologic conditions. 16,17,18,19,20 Indirect pro-inflammatory actions may also be seen. As cholesterol crystals form, they typically become coated by proteins, including complement and apolipoproteins, which make them inert in the extracellular space. 21 Uncovered crystals have the ability to cleave complement factors, including C3 and C5. This action can enhance the local inflammatory response by stimulating endothelial cells to express E-selectin on their surface, which facilitates the ingress of circulating neutrophils into the interstitial space surrounding the plaque core and directly activates neutrophils. If the inflammatory stimulus is low grade, it leads to chronic inflammation that results in progressive thickening, calcification, and deformity of the vessel wall. Inmore advanced plaque, the inflammatory reaction may be enhanced and sufficient to result in either erosion or complete disruption of the plaque, leading to atherothrombosis. 12,13,22 The pro-inflammatory NLRP3-mediated response to cholesterol crystals within plaque therefore has similarities to the crystal-induced inflammation caused by sodium urate deposition. 23 Hyperuricemia leading to the precipitation of monosodium urate crystals in the extremities causes gout. This condition has been treated for centuries in an effective manner with colchicine. 24,25 The complexity of the inflammatory elements in atherosclerosis is now better understood but still only partially reflected by the interplay of complement, interleukins, and neutrophils. We know that inhibition of one or more of these inflammatory elements can translate into improvement in clinical outcomes in