Macrophage type-I and type-II class-A scavenger receptors (MSR-A) are implicated in the pathological deposition of cholesterol during atherogenesis as a result of receptor-mediated uptake of modified low-density lipoproteins (mLDL). MSR-A can bind an extraordinarily wide range of ligands, including bacterial pathogens, and also mediates cation-independent macrophage adhesion in vitro. Here we show that targeted disruption of the MSR-A gene in mice results in a reduction in the size of atherosclerotic lesions in an animal deficient in apolipoprotein E. Macrophages from MSR-A-deficient mice show a marked decrease in mLDL uptake in vitro, whereas mLDL clearance from plasma occurs at a normal rate, indicating that there may be alternative mechanisms for removing mLDL from the circulation. In addition, MSR-A-knockout mice show an increased susceptibility to infection with Listeria monocytogenes or herpes simplex virus type-1, indicating that MSR-A may play a part in host defence against pathogens.

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Macrophages are a heterogeneous population differing in their site of location, morphology and function. They develop from hematopoietic stem cells originating in both fetal and bone marrow hematopoiesis. In yolk sac and early hepatic hematopoiesis, primitive/fetal macrophages develop from hematopoietic stem cells, bypassing the stage of monocytic cells (monoblasts, promonocytes and monocytes), possess proliferative capacity and differentiate into resident macrophages in tissues in late ontogeny. Monocytic cells develop in hepatic hematopoiesis after the development of primitive/fetal macrophages, then move into the bone marrow in late ontogeny, forming a monocyte-derived macrophage population in tissues. Like monocytes, the monocyte-derived macrophages have no proliferative potential and are short-lived, whereas the resident macrophages are long-lived in tissue, possess proliferative capacity and can be sustained by self-renewal. In adult life, the bone marrow releases macrophage precursors (immature myeloid cells) and monocytes into peripheral blood, but normally not monoblasts or promonocyts. The myeloid precursor cells migrate into tissues and differentiate into resident macrophages or related cells in situ due to macrophage differentiation or growth factors, such as M-CSF and GM-CSF, produced in situ and/or supplied humorally. Monocytes, however, migrate into tissues in response to inflammatory stimuli and differentiate into exudate macrophages. The distinct differentiation pathways of monocyte/macrophages, resident macrophages, other macrophage subpopulations, and macrophage-related cells are reviewed together with the heterogeneity of macrophage precursor cells.

Primitive macrophages first appear in the blood islands of the mouse yolk sac on the ninth day of gestation. After the tenth day of fetal life, these cells differentiate into fetal macrophages and become mature, with the development of intracellular organelles. They appear in the mesenchymal layer and further immigrate into the extraembryonic coelom. The fetal macrophages do not show any cytochemical peroxidase or 5'-nucleotidase activity, and they possess a marked proliferative capacity. Promonocytes or monocytes that have an incomplete ultrastructure emerge in the blood islands of the yolk sac a day after the occurrence of the fetal macrophages. These events suggest that fetal macrophages differentiate from primitive macrophages before the development of promonocytes or monocytes in the mouse yolk sac; they actively proliferate and are colonized into the embryonic tissues. These results also indicate that the ontogeny of the monocyte/macrophage is different in the early embryo compared with its later developmental stages.

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