The Phylogeny, Ontogeny, and Organ-specific Differentiation of Macrophages in the Developing Intestine.

Abstract

Macrophages are large highly motile phagocytic leukocytes that appear early during embryonic development and have been conserved during evolution. The developmental roles of macrophages were first described nearly a century ago, at about the time these cells were being identified as central effectors in phagocytosis and elimination of microbes. Since then, we have made considerable progress in understanding the development of various subsets of macrophages and the diverse roles these cells play in both physiology and disease. This article reviews the phylogeny and the ontogeny of macrophages with a particular focus on the gastrointestinal tract, and the role of these mucosal macrophages in immune surveillance, innate immunity, homeostasis, tissue remodeling, angiogenesis, and repair of damaged tissues. We also discuss the importance of these macrophages in the inflammatory changes in neonatal necrotizing enterocolitis (NEC). This article presents a combination of our own peer-reviewed clinical and preclinical studies, with an extensive review of the literature using the databases PubMed, EMBASE, and Scopus. Macrophages were first described at the beginning of the previous century by Paul Ehrlich and Ilya Metchnikoff as important mediators of innate immunity.1 The name "macrophages" or "big eaters" came from the Greek words, "makros" or large, and "phagein" or eat.2 Macrophages are large cells with an irregular cell shape, oval- or kidney-shaped nucleus, cytoplasmic vesicles, central nucleus, and high cytoplasm-to-nucleus ratio.3 These cells are highly phagocytic and motile, and modulate immune responses by releasing various mediators.4 The term mononuclear phagocyte includes lineage-committed bone marrow precursors, circulating monocytes, resident macrophages, and dendritic cells (DCs).5 In this review, we have focused on the macrophage lineage as it expands and matures first, in utero, and plays an important role in the innate immune responses of newborn infants.