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Differential expression of scavenger receptor isoforms during monocyte-macrophage differentiation and foam cell
Y Geng1, T Kodama, G K Hansson
1Department of Clinical Chemistry, Gothenburg University, Sahlgren's Hospital, Sweden.
Abstract:
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 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.
Insights
Scavenger receptors, like the macrophage scavenger receptor (MSR), bind modified lipoproteins. Type I MSR expression increases during monocyte to macrophage differentiation, enhancing acetylated LDL uptake and foam cell formation.
Area of Science:
- Cell Biology
- Molecular Biology
- Immunology
Background:
- Scavenger receptors (SRs) are crucial for binding and internalizing modified lipoproteins.
- Human macrophage scavenger receptor (MSR) exists as type I and type II isoforms, arising from alternative splicing.
- Understanding MSR isoform regulation during immune cell differentiation is key to lipid metabolism research.
Purpose of the Study:
- To investigate the expression patterns of MSR type I and type II isoforms during monocyte differentiation into macrophages and foam cells.
- To determine the role of MSR isoforms in the uptake of acetylated low-density lipoprotein (LDL).
Main Methods:
- cDNA cloning of human MSR.
- Analysis of MSR mRNA and protein expression during monocyte-macrophage-foam cell differentiation.
- Flow cytometry for cell surface protein analysis.
- Quantitative analysis of MSR mRNA species.
Main Results:
- Both MSR isoforms are expressed at low, equal levels on monocytes.
- Monocyte to macrophage differentiation shows a selective, rapid increase in type I MSR mRNA.
- Type I MSR protein increases on the cell surface during differentiation, correlating with enhanced acetylated LDL uptake.
- Type I MSR mRNA dominates during foam cell formation.
Conclusions:
- Selective upregulation of type I MSR at the mRNA level drives increased modified LDL uptake during monocyte to macrophage differentiation.
- Increased type I MSR expression is implicated in the pathogenesis of foam cell formation.
- Differential expression of MSR isoforms plays a critical role in lipid handling by macrophages.