Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1beta and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1beta has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway.Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1beta from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1beta was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1beta secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1beta secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization.The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions

Stress analysis on carotid atherosclerotic plaques by fluid structure interaction

This chapter discusses stress analysis on carotid atherosclerotic plaques by fluid structure interaction. It is part of a collection which focus on the management of the atherosclerotic disease. The coverage of the book spans from histological presentation of the various stages of atherosclerotic lesions to the earliest studies in atherosclerosis therapy, from advanced clinical diagnosis to monitoring, follow-up, and home-care of the atherosclerotic patient. The book shows well-established diagnostic techniques covering several medical imaging modalities such as Ultrasounds, IVUS, MRI, Computer Tomography, along with new trends in early and advanced atherosclerosis diagnosis (innovative drugs and tissue characterization procedures). Surgical standards will be presented along with innovative experimental trials for the treatment of the atherosclerotic patient. The book will also cover emerging techniques based on molecular imaging and vibro-acoustics