Macrophages play a key role in host defense against invading pathogens and tumor growth. In the activated state, macrophages undergo extensive biochemical changes, many of which involve alterations in secretory rates and cell surface markers. At sites of inflammation, for example, the macrophages infiltrate the area and begin to flood the surrounding area with hydrolytic enzymes. It has recently been shown that macrophages in vivo and in vitro have the capacity to clear hydrolases from the extracellular milieu by receptor-mediated endocytosis. It has been suggested that this receptor (the mannose-specific receptor) is involved in regulating extracellular and intracellular levels of lysosomal enzymes. In addition, this receptor is closely modulated: when high levels of extracellular enzymes are required (following activation), the receptor activity declines; when low levels of enzymes result (following glucocorticoid treatment), receptor levels are high. Thus, the mannose receptor on macrophages offers a unique system to study receptor biosynthesis, turnover, and modulation during macrophage activation and treatment with glucocorticoids. The objective of this proposal is to study the mechanism of mannose receptor modulation on human macrophages in vitro, and to investigate the cell biological and biochemical alterations in receptor function following treatment with activating agents and dexamethasone. It is hoped that the experiments outlined in this proposal will help to define a physiological role for the mannose receptor, and aid in understanding the mechanism of modulation of macrophage function, in general.
