The Ontogeny of Monocyte Subsets

Abstract

Classical and non-classical monocytes, and the macrophages and monocyte-derived dendritic cells they produce, play key roles in host defense against pathogens, immune regulation, tissue repair and many other processes throughout the body. Recent studies have revealed previously unappreciated heterogeneity among monocytes that may explain this functional diversity, but our understanding of mechanisms controlling the functional programming of distinct monocyte subsets remains incomplete. Resolving monocyte heterogeneity and understanding how their functional identity is determined holds great promise for therapeutic immune modulation. In this review, we examine how monocyte origins and developmental influences shape the phenotypic and functional characteristics of monocyte subsets during homeostasis and in the context of infection, inflammation, and cancer. We consider how extrinsic signals and transcriptional regulators impact monocyte production and functional programming, as well as the influence of epigenetic and metabolic mechanisms. We also examine the evidence that functionally distinct monocyte subsets are produced via different developmental pathways during homeostasis and that inflammatory stimuli differentially target progenitors during an emergency response. We highlight the need for a more comprehensive understanding of the relationship between monocyte ontogeny and heterogeneity, including multiparametric single-cell profiling and functional analyses. Studies defining mechanisms of monocyte subset production and maintenance of unique monocyte identities have the potential to facilitate the design of therapeutic interventions to target specific monocyte subsets in a variety of disease contexts, including infectious and inflammatory diseases, cancer, and aging.

Keywords: bone marrow; monocyte ontogeny; monocyte progenitors; monocyte subsets; monopoiesis.

Figure 1

Pathways of myeloid cell differentiation. In the steady-state, distinct mouse monocyte subsets arise independently from common myeloid progenitors (CMPs; LKS⁻ CD34⁺ FcγR^lo Flt3⁺ CD115^lo cells) via granulocyte-monocyte progenitors (GMPs; LKS⁻ CD34⁺ FcγR^hi Ly6C⁻) and monocyte-DC progenitors (MDPs; LKS⁻ CD34⁺ FcγR^lo Flt3⁺ CD115^hi). GMPs also produce neutrophils (via granulocyte progenitors, GPs), and MDPs yield cDCs and pDCs (via common DC progenitors, CDPs). Functionally distinct subsets of classical monocytes (Ly6C^hi in mice) are produced by both GMPs and MDPs. Non-classical (Ly6C⁻) monocytes and macrophages, also arise via both pathways and may exhibit functional differences. In contrast, monocyte-derived DCs (moDCs, which are ontogenetically and functionally distinct from cDCs and pDCs) arise exclusively from MDP-derived monocytes, and GMPs produce a neutrophil-like subset of classical monocytes. Monocyte-committed progenitors arising from GMPs (known as MPs) and MDPs (known as cMoPs) are both found in the LKS⁻ CD34⁺ FcγR^hi Ly6C⁺ CD115^hi fraction of mouse bone marrow; it is not currently possible to separate them using surface markers, but MPs and cMoPs are revealed as distinct cell clusters by single-cell RNA sequencing.

Figure 2

Emergency monopoiesis. Under emergency or stress conditions, functionally distinct monocyte subsets may arise in the bone marrow or spleen, and production of monocyte (and other myeloid cell) subsets may be selectively enhanced. (A) In response to intestinal T. gondii infection in mice, MHCII⁺ Sca-1⁺ CX3CR1⁻ Ly6C^hi monocytes are produced by monocyte-committed progenitors that, unlike their steady-state counterparts, also express MHCII and Sca-1 (40). (B) LPS and CpG promote monocyte production by murine GMPs and MDPs, respectively; LPS also stimulates neutrophil production by GMPs, whereas CpG enhances cDC production by MDPs (11).