UC San Diego

Macrophages are professional phagocytes that play an essential role in the host defense against pathogens, on the other hand these cells are at the center of lipid and inflammation biology as demonstrated by their role in the development of atherosclerosis. The intricacies of the interaction between lipid homeostasis and the host immune system are not yet fully elucidated. Current literature supports a role for intracellular cholesterol content and distribution in the regulation of cellular functions such as : migration, membrane trafficking and signaling. In the process of atherogenesis, early stages of lesion development are characterized by accumulation of esterified cholesterol in macrophage cytoplasmic lipid droplets, as the disease progresses intracellular cholesterol redistribution ensues with buildup of free cholesterol in other cellular compartments, such as lysosomes and the plasma membrane. In this study, we have investigated the role that macrophage intracellular cholesterol homeostasis plays on Fc[gamma] receptor (Fc[gamma]R)-mediated phagocytosis. Our experimental model consisted of murine macrophages (i.e. J774.1 cells and isolated naïve peritoneal macrophages) submitted to several different pharmacological strategies to induce cholesterol redistribution and accumulation in late endosomes/lysosomes. Cells were subsequently challenged with opsonized bacterial particles to determine Fc[gamma]R -mediated phagocytic capacity. We found that cholesterol accumulation in late endosomes/lysosomes leads to a significant decrease of this main function. We further identified the mechanism for this defect to be associated with decreased expression of all three subtypes of the receptor (i.e. Fc[gamma]RI, Fc[gamma]RII and Fc[gamma]RIII) both at the protein as well as the mRNA level. Moreover, this effect was exerted at the level of transcriptional regulation of the expression of these receptors by impairing expression and recruitment of two essential transcription factors, PU.1 and Stat1. In addition, this pattern of cholesterol accumulation is associated with alterations in the cholesterol homeostasis transcriptional program. In summary, this work demonstrates the critical role of normal cholesterol homeostasis in the regulation of Fc[gamma]R-mediated phagocytosis, a critical function of the host immune response to pathogens