Low Density Lipoprotein Metabolism by Human Macrophages Activated with Low Density Lipoprotein Immune Complexes: A Possible Mechanism of Foam Cell Formation
Human monocytes are known to be multifunctional cells that combine a variety of functions, including phagocytosis, antigen processing and presentation to immune cells, secretion of a large number of bioactive products with significant roles in the immune and inflammatory reactions, and the ability to kill tumor cells and other abnormal cells by a variety of mechanisms, including antibody-dependent cell-mediated cytotoxicity (1-5). Tissue macrophages are believed to derive from circulating monocytes, although the two types of cells differ by a variety of morphological and functional criteria (6-10). The role of macrophages is not always well understood, since it combines potentially useful properties related to its ability to ingest and process foreign and altered materials with the capacity to secrete large amounts of mediators having the potential to cause inflammatory changes and tissue damage in general (11-14). In atherosclerosis, substantial evidence has been gathered suggesting that the foam cells seen in early atherosclerotic plaques are derived from monocytes/macrophages (15-18). The formation and subendothelial accumulation of foam cells are believed to represent a critical event in the onset of atheromatous plaque formation (19). Some interesting correlations can be drawn between the involvement of macrophages in the pathogenesis of atherosclerosis and increasing evidence suggesting that immunologic mechanisms may influence the development or evolution of this pathologic process. In the early 1970s, it was postulated that immune mechanisms involving circulating immune complexes could contribute to the pathogenesis of atherosclerosis (20). The evidence supporting this role of immune complexes was both experimental (animals undergoing serum sickness and given a lipid-rich diet developed accelerated atherosclerosis [21]) and clinical (patients with IgA myelomas with anti-lipoprotein activity had massive hyperlipemia and accelerated atherosclerosis [22]). More recently, it was also shown that immune complexes (IC)1 involving low density lipoprotein (LDL) induce profound changes on cholesterol metabolism at the cellular level (23). Further support for the involvement of IC in the pathogenesis of atherosclerosis has been recently obtained by Szondy et al. (24), who demonstrated increased levels of IC and anti-LDL antibodies in patients with clinical manifestations of coronary heart disease. The possibility that IC interactions with macrophages may lead to their activation and, therefore, play a pathogenic role in the development of atherosclerosis is extremely challenging. Until recently, the mechanism proposed to explain how monocyte-derived macrophages could be transformed into foam cells has focused upon the interaction between macrophages and modified LDL or lipoproteins of abnormal composition, such as β-very low density lipoproteins (VLDL). Modified LDL can be taken up in a nonregulated fashion via the scavenger receptor, resulting in the intracellular accumulation of cholesteryl esters (CE) and in the formation of a foam cell. In contrast, it has been observed that cultured macrophages exposed to native LDL (NLDL) do not accumulate CE due to the stringent regulation of LDL receptors. However, it has been recently shown that in certain conditions, macrophages exposed to native LDL may accumulate CE. In our laboratory, we have shown that human macrophages stimulated with microbial or microbial-related products have an increased uptake of N-LDL and accumulated CE (25). Tabas et al. (26) observed increased uptake of N-LDL and concomitant CE accumulation in J774 cells, a mouse macrophage-like tumor cell line. They postulated that this was due to the enhanced metabolic activity of this tumor cell line (26). Klimov, et al. (27) had shown excessive CE accumulation in mouse peritoneal macrophages exposed to LDL immune complexes compared with control cells. A common denominator for all these observations is the known ability of microbial products and immune complexes to activate macrophages. Therefore, we decided to examine the effect of macrophage activation on N-LDL metabolism. More specifically, we wanted to investigate the effect of LDL-anti-LDL IC on N-LDL and cholesterol metabolism in human macrophages, and determine whether this type of IC can induce the transformation of human macrophages into foam cells contributing to the development of atherosclerosis
