Scavenger receptors in atherosclerosis: new answers, new questions.

Abstract

The existence of a cell surface receptor, now known as the macrophage scavenger receptor A I/II (MSR-A), was inferred from early studies based on ligand binding analyses. Description of this binding activity, with acetylated low density lipoprotein (LDL) used as a ligand, was important because it provided a mechanism for the formation of foam cells in vivo and because the activity of this receptor was not downregulated by expanding cellular cholesterol stores as had been recently shown for the LDL receptor. The presence of acetylated LDL receptor binding activity, predominantly on macrophage-type cells, helped to underscore the importance of the macrophage in atherogenesis and stimulated further investigation of macrophage function in the vessel wall. The description of this activity also helped to fuel investigative efforts to identify a potential in vivo ligand, and the various forms of oxidized LDL were soon suggested as physiological ligands for this receptor. Thus, the MSR-A has already shaped investigative efforts into the mechanisms of atherosclerosis. Now that MSR-A has been cloned, attempts to further understand its role in atherogenesis with the use of mice deficient in its expression have been undertaken. An early report by Suzuki et al1 demonstrated that compared with control apolipoprotein E (apoE)–knockout mice, mice with macrophage scavenger receptor A I/II (MSR-A) deficiency, on an apoE-deficient background, exhibited a 60% decrease in lesions; this observation was consistent with a proatherogenic role for this receptor in vivo. There were a number of surprising findings in their study. Even though acetylated LDL degradation by macrophages was reduced substantially, there was no difference in the metabolism of acetylated LDL in vivo. In spite of this, the plasma cholesterol level in double-knockout mice was higher than in apoE-knockout mice. These double-knockout mice were also found to have increased susceptibility to infection, and the macrophages …