Two major theories concerning the development and differentiation of macrophages-the reticuloendothelial system proposed by Aschoff (1924) and the mononuclear phagocyte system developed by van Furth (1972)-are critically reviewed. Phylogenetically, mononuclear phagocytic cells (macrophages) develop in all animals; monocytes are not detected in invertebrates, and both macrophages and monocytes appear in vertebrates. The phylogenetic principle that the development and differentiation of macrophages precede those of monocytes during the evolutionary processes of animals applies to human and murine ontogeny of macrophages. In early ontogeny, macrophages develop from hematopoietic stem cells during yolk sac hematopoiesis, and the stage of monocytic cells is bypassed. Monocytic cells develop during hepatic hematopoiesis, and their development proceeds from the middle stage of ontogeny.
In postnatal and adult life, macrophages are differentiated from macrophage precursor cells at different stages or through different pathways of differentiation. In addition to developing via the differentiation pathway of monocytic cells into macrophages, tissue macrophages develop from macrophage precursor cells at or before the stage of granulocyte/macrophage colony-forming cells, and some macrophage populations are derived from B lymphoid precursor cells. Dendritic cells are also derived from different precursor cells and are classified into myeloid dendritic cells, monocyte-derived dendritic cells, and lymphoid dendritic cells according to their precursor cell origin. Thus, macrophages and their related cells are believed to be differentiated from hematopoietic stem cells through multiple pathways. Finally, the roles of two major macrophage populations, Kupffer cells and monocyte-derived macrophages, in hepatic granuloma formation are analyzed by considering various mouse models.