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.

Keywords: Blood counts; Inflammation; Macrophages; Monocytes; Organ injury; Signaling.

Figs 1A and B:

Intestinal macrophage populations in neonatal mice. We used flow cytometry to examine intestinal lysates from mouse pups with normal intestine and from others with intestinal inflammation. Macrophages were identified as the cells expressing the myeloid marker CD11b and the macrophage marker, F4/80. The normal intestine showed two distinct pools of macrophages, one of mature macrophages that expressed F4/80 at high levels and likely represents YS-derived cells. There was a second F4/80^mid subset consistent with MDMs. During inflammation, the MDM pool got enlarged. Some newly recruited F4/80^low monocytes were also seen (expressed high levels of the monocyte marker Ly6C; not shown)

Fig. 2:

Fluorescence photomicrograph (1000×) of a villus in preterm (26 weeks) human intestine shows that macrophages (HAM56, red) express CD14 (green). CD14 is an important mediator in the bacterial lipopolysaccharide (LPS)-stimulated signaling pathways. These findings are important because macrophages in the adult human intestine do not express CD14 and are unresponsive to LPS. Nuclei are stained blue (4′,6-diamidino-2-phenylindole, or DAPI, is a fluorescent stain that binds adenine–thymine-rich regions in DNA)

Flowchart 1:

Phylogeny of macrophages. Schematic figure shows the development of macrophage-like cells and macrophages across evolution. The orange-colored boxes with eukaryota, animalia, triploblasts, deuterostomia, chordata, and vertebrata traces the evolution of vertebrate animals such as humans. The green font indicates key events in the development of immunity. Upper-case, red-font labels show the evolution of phagocytes. For each category of animals, one or more representative organisms are listed below in black font

Flowchart 2:

Ontogeny of gut macrophages. Schematic figure shows the development of the three major categories of macrophages in the human embryo, from progenitors in the yolk sac (YS), from the YS endothelium, and from the hematopoietic stem cells (HSCs). A subset of the HSCs evolves into monocytes, and current understanding suggests the classical CD14⁺⁺ monocytes differentiate into the M1 inflammatory and M2 immunoregulatory macrophages. There is a possibility that the CD14lowCD16 monocytes may (also) evolve into the immunoregulatory macrophages, which is shown as a broken arrow. Increasing information suggests that the M2 macrophages may be a heterogenous group comprised of multiple subsets

Flowchart 3:

Classification of gut macrophages by location. Schematic shows the location, classification by location or shape, and the best-known function