Plasticity of monocyte development and monocyte fates
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.
References (151)
- et al.
Developmental and functional heterogeneity of monocytes
Immunity
(2018) - et al.
Tissue-resident macrophage ontogeny and homeostasis
Immunity
(2016) - et al.
Microglia biology: one century of evolving concepts
Cell
(2019) - et al.
Identification and characterization of a novel monocyte subpopulation in human peripheral blood
Blood
(1989) Heterogeneity of human blood monocytes: the CD14+CD16+ subpopulation
Immunol. Today
(1996)Monocyte subsets in man and other species
Cell Immunol.
(2014)- et al.
Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates
Blood.
(2012) - et al.
Identification of two subpopulations of rat monocytes expressing disparate molecular forms and quantities of CD43
Cell Immunol.
(1995) - et al.
Comparison of gene expression profiles between human and mouse monocyte subsets
Blood
(2010) - et al.
Intestinal lamina propria dendritic cell subsets have different origin and functions
Immunity
(2009)
Nonclassical Ly6C− monocytes Drive the development of inflammatory arthritis in mice
Cell Rep.
The heterogeneity of Ly6Chi monocytes controls their differentiation into iNOS+ macrophages or monocyte-derived dendritic cells
Immunity
Ly6Chi monocytes in the inflamed colon Give rise to proinflammatory effector cells and migratory antigen-presenting cells
Immunity
IRF8 acts in lineage-committed rather than oligopotent progenitors to control neutrophil vs monocyte production
Blood
Transcriptional heterogeneity and lineage commitment in myeloid progenitors
Cell
Bone-marrow-resident NK cells prime monocytes for regulatory function during infection
Immunity
Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment
Cell
Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis
Immunity
Towards the better understanding of myelopoiesis using single-cell technologies
Mol. Immunol.
Origin and function of synovial macrophage subsets during inflammatory joint disease
Adv. Immunol.
Embryonic and adult-derived resident cardiac macrophages are maintained through distinct mechanisms at steady state and during inflammation
Immunity
Macrophages contribute to the spermatogonial niche in the adult testis
Cell Rep.
Neuro-immune interactions Drive tissue programming in intestinal macrophages
Cell
Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility
Cell
Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis
Immunity
The origin and kinetics of mononuclear phagocytes
J. Exp. Med.
Fetal monocytes and the origins of tissue-resident macrophages
Cell Immunol.
Monocyte heterogeneity underlying phenotypic changes in monocytes according to SIV disease stage
J Leukocyte Biol.
The antibody MY4 recognizes CD14 on porcine monocytes and macrophages
Scand. J. Immunol.
Inflammatory chemokine transport and presentation in HEV a remote control mechanism for monocyte recruitment to lymph nodes in inflamed tissues
J Exp Medicine.
Phenotypic and functional heterogeneity of bovine blood monocytes
Plos One
Analysis of fractalkine receptor CX3CR1 function by targeted deletion and Green fluorescent protein reporter Gene insertion
Mol. Cell Biol.
Genomic characterization of murine monocytes reveals C/EBPβ transcription factor dependence of Ly6C− cells
Immunity
Lineage tracing on transcriptional landscapes links state to fate during differentiation
Science
Granulocyte-monocyte progenitors and monocyte-dendritic cell progenitors independently produce functionally distinct monocytes
Immunity.
Defining murine monocyte differentiation into colonic and ileal macrophages
Elife
Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior
Science
The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions
J. Exp. Med.
The cardiac microenvironment instructs divergent monocyte fates and functions in myocarditis
Cell Rep.
Non-classical tissue monocytes and two functionally distinct populations of interstitial macrophages populate the mouse lung
Nat Commun.
Identification of splenic Reservoir monocytes and their deployment to inflammatory sites
Science.
Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2
Nat Immunol.
Origin of monocytes and macrophages in a committed progenitor
Nat Immunol.
Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses
Nat Immunol.
Inflammatory type 2 cDCs acquire features of cDC1s and macrophages to orchestrate immunity to respiratory virus infection
Immunity
CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1‐inducing role of mesenteric lymph node macrophages during colitis
Eur. J. Immunol.
A clonogenic common myeloid progenitor that gives rise to all myeloid lineages
Nature
Development of CD8α-positive dendritic cells from a common myeloid progenitor
Science
Fate mapping via Ms4a3-expression history traces monocyte-derived cells
Cell
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