Cholesterol Contents in Human Macrophages Regulate Their Inflammatory Responses

Abstract

Atherosclerosis is a chronic inflammatory and lipid disorder caused by the buildup of cholesterol-loaded cells of monocyte and muscle cell origin in the arterial intima. While the relationship between excess cholesterol and macrophage behavior is well observed, the molecular mechanisms linking the two remain unclear. Therefore, characterizing the pathways from changes in intracellular cholesterol to the resulting inflammatory output is key to understanding the behavioral changes observed in human macrophages in vitro. We identified that THP-1 macrophages acutely depleted of cholesterol increase the expression of JMJD3, an H3K27me3 demethylase. By using IL-10 as a marker for immune-modulating genes and TNF-α as a marker for pro-inflammatory genes, cholesterol-depleted THP-1 macrophages responded inconsistently to LPS and echinomycin, an inhibitor of HIF-1α, as determined by RT-qPCR and ELISA. Further studies investigating other regulators and outputs of macrophage behavior linked to cellular cholesterol modification are required.