Cholesterol crystal-inflammation link confirmed in human cells
MedWire News: Cholesterol crystals are able to induce the release of inflammatory molecules from human macrophages, report Finnish researchers.
The results are in line with findings that recently emerged from an animal study, which also showed that deposition of cholesterol crystals in the arteries occurs very early in the process of atherogenesis.
This potentially offers a fresh target for preventing and treating atherosclerosis. But lead researcher of the current study, Kristiina Rajamäki (Wihuri Research Institute, Helsinki), told MedWire News that directly targeting the crystals will require a completely new approach.
"High-density lipoprotein (HDL) can effectively remove intracellular cholesterol from macrophage foam cells in atherosclerotic plaques, but HDL appears to be ineffective in removing cholesterol from the extracellular cholesterol crystals," she explained.
"Thus, the challenge to induce crystal regression is huge, and calls for novel ideas and a totally new way of thinking."
In their study, published in the journal PLoS ONE, Rajamäki and colleagues show that macrophages obtained from healthy humans are able to phagocytose cholesterol crystals, partially dissolve them, and store them as cholesteryl esters. As in the previous study, the team found that uptake of the cholesterol crystals caused rupture of the macrophages' lysosomes.
In the presence of a costimulant (lipopolysaccharide), macrophages responded to cholesterol crystals with dose-dependent release of the inflammatory mediator interleukin (IL)-1β.
They also showed upregulation of the NLRP3, CASP1 genes, which encode proteins that make up the NLRP3 inflammasome, and of the gene encoding IL-1β.
Inflammasomes are complexes of proteins that assemble in response to injurious stimuli. The complexes include caspase 1, and cause its activation and subsequent activation of other inflammatory signaling molecules.
In the THP-1 macrophage cell line, which responded to cholesterol crystals without the need for a costimulant, silencing the NLRP3 gene reduced its protein expression by 72% and completely abolished cholesterol crystal-induced IL-1β release.
Thus, the findings "strongly implicate" cholesterol crystals as a driver of inflammation in atherosclerosis, concludes the team.
"At the moment we do not know how to make them disappear from atherosclerotic plaques and, therefore, the more efficient therapeutic method may be to prevent them from forming in the first place," said Rajamäki.
"Most importantly, this could also prevent non-dangerous and innocent plaques from turning into clinically significant vulnerable plaques."
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By Eleanor McDermid