Role of phagocytosis of modified low-density lipoproteins self-associates in pro-inflammatory activation of macrophages.

Abstract

Background and Aims: Excessive accumulation of lipid inclusions in the arterial wall cells (foam cell formation) caused by modified low-density lipoprotein (LDL) is the earliest and most noticeable manifestation of atherosclerosis. The mechanisms of foam cell formation are not fully understood and can involve altered lipid uptake, impaired lipid metabolism, or both. Recently, we have identified the top 10 master regulators that are involved in the accumulation of cholesterol in cultured macrophages induced by the incubation with modified LDL. We found that most of the identified master regulators were related to the regulation of the inflammatory immune response, but not to lipid metabolism. A possible explanation for this unexpected result is a stimulation of the phagocytic activity of macrophages by modified LDL particle associates that have a relatively large size. In the current study, we investigated gene regulation in macrophages using transcriptome analysis to test the hypothesis that the primary link between the interaction of modified LDL and macrophages is stimulation of phagocytosis, which subsequently triggers the pro-inflammatory immune response.