Recent work has shed light on the diverse nature of myeloid cells. It is now recognized that subtypes of myeloid cells have varied developmental origins, such as microglia which are derived from the embryonic yolk sac and not replenished by blood-derived monocytes [1
]. Tissue macrophages, however, are derived from hematopoietic stem cells, but their expansion can either be due to local proliferation or infiltration, depending on the stimulus [2
]. While we often use the generic term “macrophage” in this review, it is quite clear that the location of the macrophage and the local environment affect gene expression and, therefore, cell phenotype.
After decades of research, it is now clear that macrophages do more than simply protect the host from foreign invaders. The known roles of myeloid lineage cells have been expanded such that innate immunity is now recognized as just one of a myriad of critical functions. This relatively new perspective on these ancient cells appears obvious in hindsight. Macrophages have evolutionary cousins in all species from invertebrates to mammals [3
], and phagocytosis was a critical development in the course of evolution. This property, or some permutation of it, emerged in invertebrates before any semblance of innate immunity () [3
]. In vertebrates, myeloid cells are found in nearly every tissue from the early stages of development, where they remain throughout the entire life of the organism. Furthermore, after injury or during disease, additional myeloid cells are recruited, even in the absence of pathogens, and disperse after repair or recovery.
Ilya Metchnikoff, the father of cellular immunology, believed in an expansive role for macrophages. He detailed the importance of phagocytic cells in clearing fungal infections from crustacea and bacterial infections from rabbits. Interestingly, he proposed that macrophages evolved first to regulate development (phagocytosing unwanted cells), and that these phagocytic traits set the stage for their evolution into effectors of innate immunity [4
]. Beyond regulating development and maintaining order, Metchnikoff suggested that macrophages played a role during injury repair [5
]. Specifically, he noted that in fish embyros injured by cauterization, the recruitment of macrophages to the injured tissue resembled their recruitment to sites of infection [5
]. These broad-ranging, seminal studies set the stage for the next century of research into macrophage biology.
Historically, several additional insights shed light on the nature of macrophages. First, characterization of the mononuclear phagocyte system (MPS) revealed how macrophages move into areas of infection or disease. By the late 1960s, monocyte extravasation (see Glossary) was well-described [6
]. Second, the discovery of “macrophage activation” detailed how macrophages increased the intensity of their response to a second infection following an initial infection. It was now clear that macrophages were more than simple bystanders performing phagocytic functions [7
]. Furthermore, macrophages have been found to produce almost every known effector molecule including PDGFs (platelet-derived growth factors), IGFs (insulin-like growth factors), HGFs (hepatocyte growth factors), FGFs (fibroblast growth factors), TGFs (transforming growth factors), CSFs (colony stimulating factors), Wnt ligands, and many immune-related molecules. The coordinated release of such factors enables macrophages to dramatically affect the cellular milieu. In this review, we summarize work that has elucidated the mechanisms behind Metchnikoff’s original hypotheses.