Origins, Biology, and Diseases of Tissue Macrophages

Abstract

Tissue-resident macrophages are present in most tissues with developmental, self-renewal, or functional attributes that do not easily fit into a textbook picture of a plastic and multifunctional macrophage originating from hematopoietic stem cells; nor does it fit a pro- versus anti-inflammatory paradigm. This review presents and discusses current knowledge on the developmental biology of macrophages from an evolutionary perspective focused on the function of macrophages, which may aid in study of developmental, inflammatory, tumoral, and degenerative diseases. We also propose a framework to investigate the functions of macrophages in vivo and discuss how inherited germline and somatic mutations may contribute to the roles of macrophages in diseases.

Keywords: genetic diseases; macrophage specification; somatic mutations; tissue metabolism; tissue-resident macrophages.

Figure 1

Evolution of phagocyte function. Phagocytes across the phylogenetic tree sense environmental cues and phagocytose cells or foreign material in an attempt to redistribute energy and remodel their environment. This core function of phagocytes is evident in the deepest branches of the Archaea phylogeny, where these ancient phagocytes are proposed to engulf other unicellular organisms to obtain nutrients. As unicellular organisms evolved and began to form colonies, phagocytes acquired specialized functions in recycling of nutrients from dead/spent cells for consumption by healthy members of the colony. At the onset of multicellularity, phagocytes gained more complexity and obtained tissue-specific functions, including recycling of heme, nucleotides, surfactants, and bones as well as remodeling of the extracellular matrix. Figure adapted from images created with BioRender.com.

Figure 2

Macrophage development and specification. Intra- and extraembryonic hemogenic endothelium develops from the mesoderm but gives rise to two developmentally distinct lineages of hematopoietic cells. EMPs emerge in the yolk sac around E8.5 and represent the first wave of definitive hematopoiesis. They migrate to the fetal liver and give rise to fetal erythrocytes and myeloid cells, including fetal macrophages, the precursors of the postnatal resident macrophages (only macrophages are depicted here). EMP-derived macrophages develop in the absence of MYB and persist in postnatal tissues as resident macrophages. Within the embryo proper, the hemogenic endothelium of large arteries gives rise to HSCs at E10.5 as the second wave of the definitive hematopoiesis. HSCs migrate first to the fetal liver, and at E17.5, to the bone marrow, where they persist and self-renew. HSCs continuously give rise to adult-type red blood cells, lymphoid cells, and myeloid cells such as granulocyte, monocyte, and dendritic cell subsets. Abbreviations: E8.5, embryonic day 8.5; EMP, erythromyeloid progenitor; HSC, hematopoietic stem cell. Figure adapted from images created with BioRender.com.

Figure 3

Germline and somatic causes of neurodegeneration. Germline mutations present in the gametes of either or both parents will be passed down to all cells of the offspring and can be detected by DNA sequencing of any tissue. A number of coding and noncoding variants affecting genes uniquely expressed in macrophages have been found to be enriched in patients with inherited forms of neurodegenerative diseases (Table 2). On the other hand, somatic mutations arise spontaneously throughout development and adulthood and will be passed down only to direct cellular progeny through differentiation and cell division. DNA mutations thus arising within EMPs or their downstream progeny will lead to mutant clones within the tissue-resident macrophage lineage. These mutations are not likely to be detected by whole-tissue genomic sequencing and require enrichment of macrophage populations prior to DNA sequencing. In particular, somatic driver mutations in genes resulting in the aberrant activation of the MAPK pathway are causative of histiocytosis. Abbreviations: EMP, erythromyeloid progenitor; MAPK, mitogen-activated protein kinase. Figure adapted from images created with BioRender.com.