Elsevier

Immunology Letters

Volume 227, November 2020, Pages 66-78
Immunology Letters

Plasticity of monocyte development and monocyte fates

https://doi.org/10.1016/j.imlet.2020.07.007Get rights and content

Highlights

  • Monocytes are generated in the bone marrow from GMP and MDP, yielding potential functional distinct progeny.

  • Following injury, monocytes are recruited to peripheral tissues and give rise to effector cells that can promote and resolve inflammation.

  • In steady state classical monocytes give in the vasculature rise to patrolling cells.

  • Selected macrophage compartments in barrier tissues and other sites are in steady state replenished by monocytes.

Abstract

Monocytes are circulating myeloid immune precursor cells that are generated in the bone marrow. Mature monocytes are released into the circulation and, in case of need, recruited to peripheral sites of inflammation to differentiate into monocyte-derived effector cells. In absence of overt inflammation, monocytes also extravasate into selected tissues, where they complement tissue-resident macrophage compartments. Adjustment of these homeostatic monocyte infiltrates to local environment is critical to maintain health, as best established for the intestine. Defined gene expression changes that differ between gut segments presumably help strike the fine balance between the crucial function of these monocyte-derived macrophages as tissue rheostats and their detrimental hyperactivation. Environmental factors that dictate local monocyte differentiation remain incompletely understood. Definition of the latter could aid our general understanding of in vivo monocyte functions and their relation to inflammatory disorders. In this review, we summarize recent advances in our understanding of monocyte subsets, their differentiation into tissue macrophages, and selected contributions of monocyte-derived cells to steady-state physiology. Moreover, we will discuss emerging evidence for an intriguing bifurcation of monocyte development in the bone marrow and potential functional implications. Emphasis will be given to points of controversies, but we will largely focus on the healthy organism. For a discussion of monocyte and macrophage contributions to inflammatory conditions, we refer the reader to other dedicated reviews.

Section snippets

Monocytes - their subsets and fates

Already three decades ago, human monocytes were reported to come in two main flavors: CD14+ monocytes (subsequently further subdivided into CD16+ and CD16 cells [6]) and CD14lowCD16+ monocytes [7,8]. The existence of blood monocyte subsets has now been confirmed for many other mammalian species [9], including non-human primates [10,11], pigs [12], rodents [13,14], and cows [15], albeit the cells often display distinct markers. In mice, the two main blood monocyte subsets are now defined as Ly6C

Monocyte development – emerging complexity

Monocytes arise in the BM from hematopoietic stem cells (HSC) that, following asymmetric division, give rise to the common myeloid progenitors (CMP) through a number of pluripotent intermediates. CMP differentiate into myeloid-lineage-dedicated granulocyte and macrophage progenitors (GMP) [36,37] as well as macrophage and DC progenitors (MDP) that constitute a select lineage from GMP [38,39]. Following their discovery in 2006 [39], MDP were long believed to be the only monocyte progenitors in

Monocyte fates – plasticity is the name of the game

Classical Ly6Chigh monocytes in the mouse are short-lived precursor cells with an estimated half-life of 20 h [59]. The characteristic short lifespan of these cells was linked to expression of a long non-coding RNA, termed Morrbid, regulating expression of pro-apoptotic Bim [62]. Upon inflammation, Ly6Chigh monocytes extravasate into the tissue to acutely contribute to the early inflammatory response or, alternatively, differentiate into longer-lived macrophages or DC-like cells [2]. As highly

A homeostatic monocyte fate - gut macrophages

The vertebrate gut can be subdivided into small and large intestine (SI, LI) which differ anatomically, host distinct microbiota, and differentially contribute to the absorption and digestion of dietary nutrients [103]. Responding to the commensal microbiota and their products, the gut is constantly exposed to low-grade inflammation - a setting requiring tight, yet dynamic regulation of immune homeostasis which is coordinated in part by macrophages. Differentiation of murine Ly6Chigh monocytes

Cell-intrinsic and -extrinsic factors driving monocyte differentiation in the gut

The considerable heterogeneity of tissue macrophages, both with respect to their transcriptomes and chromatin landscapes [55], led to the proposal that macrophages are shaped by their respective tissue environments, rather than deriving from distinct precursor cells in the BM [[106], [107], [108]]. Indeed, macrophages gradually acquire their respective signatures under the influence of local cues, even though the latter often remain to be elucidated. Work originally focused on the definition of

The impact of metabolites on monocyte-to-macrophage transition

Recent years have seen major advance in microbiome research. Particularly in the gut, commensals likely exert a major influence on immune homeostasis and macrophages in particular [73,93,98]. The exact mechanisms by which microbiota shape the immune cell pool remain incompletely understood. In addition to direct cell-cell contact between microbes and immune cells, bacterial metabolites might drive immune crosstalk and thereby also monocyte-to-macrophage differentiation.

Exposure of colonic

A special case of monocyte-derived cells: the patrolling Ly6Clow monocytes

In the above we focused on gut macrophages as a steady-state progeny of classical Ly6Chigh monocytes. A second such homeostatic product of these cells is presented by Ly6Clow monocytes that persist in the blood with a half-life of up to 14 days and patrol the blood vessel walls [22,59,133]. Of note, Ly6Clow monocytes have been observed in the mouse BM although non-classical monocytes are absent from human BM [134]. BrdU pulse labeling data suggest that the rare Ly6Clow monocytes in the murine

Quorum sensing in monocytes and macrophages

An interesting and largely unexplored aspect of monocyte and macrophage biology is the fact that cell numbers remain constant which seems critical for function [85,141]. The phenomenon of gauging a population density, the so-called ‘quorum sensing’, and its integration with the regulation of gene expression, was first described in bacteria [[142], [143], [144]]. Mechanistically, bacteria release a soluble molecule, termed autoinducer, into their environment that acts as a surrogate marker for

Concluding remark

Monocytes are critical key players in inflammation and in the maintenance of tissue macrophages. Given their evanescence and plasticity, the study of monocytes remains a formidable challenge. Over the last decade, insights provided by imaging approaches and fate mapping in respective animal models have allowed major advances. Emerging data, however, suggest that this journey is far from over and there remains much to be learned about these intriguing cells. This includes potential parallel

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgment

The Jung laboratory is supported by the Israel Science Foundation (887/11), the Deutsche Forschungsgemeinschaft (DFG) (CRC/TRR167 ‘NeuroMac’), and the MINERVA foundation.

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