Influence of the cytocidal macrophage phenotype on the degradation of acetylated low density lipoproteins: Dual regulation of scavenger receptor activity and of intracellular degradation of endocytosed ligand

Abstract

The appearance of lipid-laden macrophages is a characteristic feature in the development of the atherosclerotic plaque. The functional status of macrophages located within the intima of atherosclerotic lesions is as yet unknown; nevertheless, macrophages are known to be exceedingly responsive to their environment and can differentiate to different functional states. The objective of this study was to determine the influence of two definable macrophage functional states, namely the IFN-primed state and the cytocidal state, on the capacity of macrophages to bind and degrade lipoproteins. We report that priming of macrophages with IFN-β or IFN-γ failed to influence the ability of macrophages to degrade native low density lipoprotein or acetylated low density lipoprotein (AcLDL). However, challenge with stimuli that induce expression of the cytocidal state (poly[I:C] and LPS) resulted in a marked inhibition of the capacity of the cells to degrade both lipoproteins. The poly[I:C]-induced inhibition of 125I-AcLDL degradation was accompanied by a proportional decrease in the binding of the ligand to its receptor which Scatchard analysis revealed was due to a decrease in receptor number rather than a change in receptor affinity for 125I-AcLDL. However, in addition to the down-regulation of receptor activity, the degradation of endocytosed 125I-AcLDL was also suppressed in macrophages that had been exposed to poly[I:C]. This latter observation suggests that the degradation of endocytosed lipid is also regulated at a second, previously unidentified level, independent of the availability of cell surface ligand receptors. We speculate that this down-regulation in the intracellular hydrolysis of endocytosed lipid may account for the observed accumulation of 125I-AcLDL in these Cells.