Macrophage differentiation and function in health and disease.

Macrophages exist in almost all animals. In some invertebrates, mesenchymal cells, endothelial cells or fibroblast-like cells can transform into macrophages. In vertebrates, primitive macrophages first develop in yolk sac hematopoiesis and differentiate into fetal macrophages. Monocytes are differentiated from hematopoietic stem cells in the late stage of fetal hematopoietic organs and bone marrow. Macrophages serve as an effector in metabolism and host defense. Depletion of macrophages severely reduced bilirubin production and host resistance to infection. Macrophage scavenger receptors are involved in host defense. Macrophage growth factors are critical for macrophage differentiation and function. In macrophage colony-stimulating factor (M-CSF)-deficient osteopetrotic mice, monocytes, tissue macrophages and osteoclasts are deficient. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-deficient mice develop alveolar proteinosis due to impaired surfactant catabolism by alveolar macrophages. Accumulation of glucocerebroside in macrophages due to the deficiency of glucocerebrosidase in lysosomes produces Gaucher cells. Macrophages in the arterial wall incorporate chemically modified low-density lipoprotein (LDL) and transform into foam cells. Binding oxidized LDL to liver X receptor alpha (LXRalpha) upregulates the expression of its target genes, which act as cholesterol removers from macrophages. Inflammatory signals downregulate the expression of LXRalpha and enhance lipid accumulation. Thus, macrophages play a pivotal role in metabolism and host defense.