During development and throughout life, macrophages reside in many tissues of the body, contributing to both the maintenance of tissue homeostasis and the immune response following injury or pathogenic insult. In the late 1960s, van Furth and Cohn proposed that tissue-resident macrophages develop primarily from circulating, bone marrow-derived blood monocytes. This model was widely accepted until recent fate-mapping studies demonstrated that several tissue-resident macrophage populations in mice arise from HSC-independent embryonic precursors and are maintained by self-renewal. The earliest macrophages or primitive progenitors arise from early and late erythro-myeloid progenitors (EMPs) generated in the extra-embryonic yolk sac during primitive hematopoiesis at embryonic age 7.5 and 8.25 (E7.5 and E8.25). These EMPs can give rise to yolk sac-derived macrophages without passing through a monocytic intermediate and are the first to seed the fetal tissues following initiation of the blood circulation. With the exception of microglial cells in the brain, the primitive macrophages in most fetal tissues are subsequently replaced either partially or completely by fetal liver-derived monocytes. Fetal liver monocytes are generated from EMPs derived from either the yolk sac or hemogenic endothelium of the placenta and umbilical cord, or from hematopoietic stem cells (HSCs) generated in the para-aortic splanchnopleura (P-Sp) and aorta-gonad-mesonephros (AGM) regions of the embryo. These progenitors migrate to the fetal liver in two successive waves around E9.5 (EMPs) and E10.5/E11 (immature and mature HSCs) and expand, giving rise to fetal liver monocytes, which enter the circulation and differentiate into macrophages in peripheral tissues. In some tissues, including the liver, lung, skin, spleen, and peritoneum, fetal liver monocyte-derived macrophages maintain the ability to self-renew into adulthood and establish the tissue-resident population. In other tissues, such as the dermis and gut, fetal liver monocyte-derived macrophages are gradually replaced by the recruitment of bone marrow-derived monocytes generated from adult hematopoiesis beginning around E17.5.
Tissue-resident macrophages are a versatile, heterogeneous group of cells that support multiple tissue functions. Most of our knowledge about these cells has come from studies in mice, which suggest that the phenotypes and functional programs of tissue macrophages are determined by signals that they receive in their tissue microenvironments. Aside from providing the first line of defense against invading pathogens, tissue-resident macrophages have a fundamental role in maintaining tissue integrity and homeostasis. In addition, they may have specialized functions based on their locations and distinct gene expression profiles. For example, osteoclasts are bone-resident macrophages that specialize in bone resorption, while red pulp macrophages in the spleen specialize in heme degradation and iron recycling. Abnormalities in macrophage functions have been associated with a wide range of chronic inflammatory and autoimmune diseases including obesity and type II diabetes, asthma, atherosclerosis, fibrosis, cancer, inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis, suggesting that macrophages may serve as therapeutic targets. This possibility, however, requires a greater understanding of the differences in the development, phenotypes, and functions of tissue-resident macrophages.