Differential Expression of Scavenger Receptor lsoforms During Monocyte-Macrophage Differentiation and Foam Cell Formation

Scavenger receptors mediate binding and uptake of chemically modified lipoproteins. cDNA cloning of the human macrophage scavenger receptor (MSR) reveals the presence of two mRNA species, the type I and II isoforms, which are generated by 3' alternative splicing of a single MSR gene and translated into two proteins with different C-terminal domains. We studied MSR isoform expression during the differentiation from circulating monocytes to adherent macrophages and subsequently to lipid-laden foam cells. Differentiation from monocyte to macrophage was associated with a prominent increase in MSR expression on the mRNA, protein, and cell surface levels, leading to an increased uptake of acetylated low-density lipoprotein (LDL). Further analyses of mRNA and proteins revealed that both MSR isoforms were present in low and approximately equal amounts on the surface of CD14 peripheral blood monocytes; these cells had Scavenger receptors mediate the uptake and degradation of chemically modified proteins. Endotoxins, acetylated and oxidized low-density lipoprotein (LDL), maleylated albumin, and other proteins with an increased negative surface charge are bound to macrophage scavenger receptors (MSRs), internalized, and degraded in a lysosomal compartment. Degradation of modified LDL via the MSR pathway results in an increased cellular cholesterol content and the formation of cholesteryl ester droplets in the cytoplasm. The increase in intracellular cholesterol levels does not affect the expression of the receptor, and lipoprotein uptake therefore continues until the macrophage is transformed into a lipid-laden foam cell.' This contrasts with the delicate homeostatic regulation of the receptor for native LDL, which is downregulated by excess levels of intracellular cholesterol. The development of lipid-laden foam cells in atherosclerotic plaques is therefore thought to be caused by MSR-mediated uptake of modified LDL.However, MSR expression is modulated by cytokines such as interferon-y and tumor necrosis factor, which are involved in macrophage activation. It therefore appears likely that Received December 29, 1993; revision accepted February 11, 1994. From the Department of Clinical Chemistry, Gothenburg University, Sahlgren's Hospital, Gothenburg, Sweden, and the Third Department of Internal Medicine (T.K.), Faculty of Medicine, Tokyo University, Tokyo, Japan. Correspondence to Dr Goran K. Hansson, Gothenburg University, Department of Clinical Chemistry, Sahlgren's Hospital, S-413 45 Gothenburg, Sweden. approximately similar levels of type I and type II MSR mRNA species. During differentiation to macrophages, there was a rapid, selective increase in type I MSR mRNA, with type II mRNA being expressed at approximately the same level as in the monocyte. This, in turn, resulted in an increase in type I MSR protein on the cell surface during differentiation from monocyte to macrophage. Type I MSR mRNA also dominated during the transformation of macrophages to foam cells in the presence of acetylated LDL. These findings suggest that the increased uptake of modified LDL during differentiation from monocyte to macrophage is accomplished by a selective upregulation of type I MSRs on the mRNA level. The increased expression of type I MSRs may be important for foam cell formation. (Arterioscler Thromb. 1994;14:798-806.)