Macrophages are multifunctional immune cells that are present in most mammalian tissues. Fate-mapping studies in mice have demonstrated that tissue-resident macrophages arise from three potential sources, yolk sac-derived erythro-myeloid progenitors, fetal liver-derived monocytes, and bone marrow-derived monocytes. Yolk sac-derived primitive macrophages are generated in two waves from ‘early’ and ‘late’ erythro-myeloid progenitors (EMPs) in the mouse embryo at embryonic age 7.5 and 8.25 (E7.5 and E8.25). Upon establishment of the blood circulation, these primitive macrophages are the first to seed the fetal tissues. With the exception of microglia in the brain, most primitive macrophages are replaced by fetal liver-derived monocytes generated at E12.5, which migrate to the peripheral tissues and differentiate into mature macrophages. In many tissues including the liver, lung, skin, spleen, and peritoneum, fetal liver-derived macrophages maintain the ability to self-renew throughout adulthood. In some other tissues, such as the gut and the dermis, fetal liver-derived monocytes are gradually replaced by bone marrow-derived monocytes generated by adult hematopoiesis beginning at E17.5 in mice. Several tissues including the spleen, lung, central nervous system, liver, skin and bone contain more than one phenotypically distinct macrophage population, which may have different origins. Within the tissues where they reside, macrophages receive specific signals that determine their phenotypes and functional programs. These programs can subsequently be altered by stress signals. In addition, tissue infection or injury can lead to the recruitment of additional bone marrow-derived monocytes, which differentiate into inflammatory macrophages in the affected tissue and commonly outnumber the tissue-resident population(s).
Tissue-resident macrophages provide the first line of defense against invading pathogens and have a fundamental role in maintaining tissue integrity and homeostasis. They perform critical immune surveillance activities including the detection of invading microbes and phagocytosis, and are involved in initiating the immune response through antigen presentation and cytokine production. Additionally, they may also have specialized functions, based on their locations and distinct gene expression profiles.