Abstract
Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.
Highlights
The accumulation of cholesterol crystals (CC) in atherosclerotic lesions reflects the imbalance of cholesterol homeostasis
Besides apoptosis (Type I, caspase dependent) and autosis (Type II, ion channel dependent), cell death characterized by the rupture of plasma membrane (Type III) was believed to be a passive event, occurring in pathological states such as hypoxia [27, 51]
The helical structure of mixed lineage kinase domain-like kinase (MLKL) switches into a new conformation which forms uncontrolled cation channels on the membrane [54]. This type of cell death differs from conventional necrosis in its sensitivity to RIPK1 inhibition
Summary
The accumulation of cholesterol crystals (CC) in atherosclerotic lesions reflects the imbalance of cholesterol homeostasis. LDL transports esterified cholesterol from the liver to artery walls via LDL receptor. The esterified cholesterol is deposited in the subintima and becomes readily accessible to macrophages and muscle cells. Ester hydrolases in these cells convert the esterified cholesterol into its free form, leading to the crystal formation [1]. This is countered by the reverse transport mediated by HDL [2].
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