The mast cell--a potential link between inflammation and cellular cholesterol deposition in atherogenesis

Mast cells are present in the arterial intima, the site of atherogenesis. In fatty streaks (the initial stage of atherogenesis) some of these cells are detected in the close vicinity of cholesterol-loaded macrophage foam cells. To ascertain whether mast cells could be involved in the formation of foam cells, a model system was developed in which isolated rat serosal mast cells were incubated with mouse peritoneal macrophages in a medium enriched with either low density lipoproteins (LDL) or high density lipoproteins (HDL3). Stimulation of the mast cells was found to induce 50-fold enhancement of LDL uptake by the macrophages. When stimulated, mast cells exocytose their secretory granules, which lose their membranes in the process. The granules then come in contact with the medium, which dissolves their histamine, a fraction of their heparin proteoglycans and all their chondroitin sulphate proteoglycans, leaving insoluble 'granule remnants'. These remnants consist of neutral proteases embedded in a heparin proteoglycan matrix. Some of the LDL particles in the incubation medium bind to this matrix, become degraded by the matrix-bound proteases, and fuse into larger particles on the surfaces of the remnants. These LDL particles are ingested by the macrophages as they phagocytose the remnants. Simultaneously, the soluble heparin proteoglycans interact with other LDL particles, forming insoluble complexes which are also phagocytosed by the macrophages. Cholesterol from the phagocytosed LDL particles ultimately becomes esterified in the macrophages, with formation of foam cells. In addition, mast cells block the removal of cholesterol from the foam cells: the remnant enzymes proteolyse HDL particles, so lessening their ability to induce efflux of cholesterol from the foam cells. These observations suggest that mast cells play an active role in the intracellular deposition of cholesteryl esters that is characteristic of early atherosclerotic lesions.