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The fate and lifespan of human monocyte subsets in steady state and systemic inflammation

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      Abstract

      Using stable isotope labeling, Patel et al. establish the lifespan of all three human monocyte subsets that circulate in dynamic equilibrium; in steady state, classical monocytes are short-lived precursors with the potential to become intermediate and nonclassical monocytes. They highlight that systemic inflammation induces an emergency release of classical monocytes into the circulation.

      Abstract

      In humans, the monocyte pool comprises three subsets (classical, intermediate, and nonclassical) that circulate in dynamic equilibrium. The kinetics underlying their generation, differentiation, and disappearance are critical to understanding both steady-state homeostasis and inflammatory responses. Here, using human in vivo deuterium labeling, we demonstrate that classical monocytes emerge first from marrow, after a postmitotic interval of 1.6 d, and circulate for a day. Subsequent labeling of intermediate and nonclassical monocytes is consistent with a model of sequential transition. Intermediate and nonclassical monocytes have longer circulating lifespans (∼4 and ∼7 d, respectively). In a human experimental endotoxemia model, a transient but profound monocytopenia was observed; restoration of circulating monocytes was achieved by the early release of classical monocytes from bone marrow. The sequence of repopulation recapitulated the order of maturation in healthy homeostasis. This developmental relationship between monocyte subsets was verified by fate mapping grafted human classical monocytes into humanized mice, which were able to differentiate sequentially into intermediate and nonclassical cells.

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      Fate mapping analysis reveals that adult microglia derive from primitive macrophages.

      Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
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        Macrophage biology in development, homeostasis and disease.

        Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.
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          Blood monocytes consist of two principal subsets with distinct migratory properties.

          Peripheral blood monocytes are a heterogeneous population of circulating leukocytes. Using a murine adoptive transfer system to probe monocyte homing and differentiation in vivo, we identified two functional subsets among murine blood monocytes: a short-lived CX(3)CR1(lo)CCR2(+)Gr1(+) subset that is actively recruited to inflamed tissues and a CX(3)CR1(hi)CCR2(-)Gr1(-) subset characterized by CX(3)CR1-dependent recruitment to noninflamed tissues. Both subsets have the potential to differentiate into dendritic cells in vivo. The level of CX(3)CR1 expression also defines the two major human monocyte subsets, the CD14(+)CD16(-) and CD14(lo)CD16(+) monocytes, which share phenotype and homing potential with the mouse subsets. These findings raise the potential for novel therapeutic strategies in inflammatory diseases.
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            Author and article information

            Affiliations
            [1 ]Division of Medicine, University College London, University of London, London, England, UK
            [2 ]Institute for Infection and Immunity, St. George’s, University of London, London, England, UK
            [3 ]Theoretical Immunology Group, Faculty of Medicine, Imperial College London, London, England, UK
            [4 ]Department of Immunobiology, Yale University, New Haven, CT
            [5 ]Howard Hughes Medical Institute, Yale University, New Haven, CT
            [6 ]Newcastle University Medical School, Newcastle University, Newcastle Upon Tyne, England, UK
            [7 ]St. George’s University Hospitals NHS Foundation Trust, London, England, UK
            Author notes
            Correspondence to Simon Yona: s.yona@ 123456ucl.ac.uk
            [*]

            R.A. Flavell, D.W. Gilroy, B. Asquith, and D. Macallan contributed equally to this paper.

            A. Rongvaux’s present address is Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

            Journal
            J Exp Med
            J. Exp. Med
            jem
            jem
            The Journal of Experimental Medicine
            The Rockefeller University Press
            0022-1007
            1540-9538
            03 July 2017
            03 July 2017
            : 214
            : 7
            : 1913-1923
            28606987 5502436 20170355 10.1084/jem.20170355
            © 2017 Patel et al.

            This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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            Funding
            Funded by: Engineering and Physical Sciences Research Council, DOI http://dx.doi.org/10.13039/501100000266;
            Funded by: Wellcome Trust, DOI http://dx.doi.org/10.13039/100004440;
            Funded by: Medical Research Council, DOI http://dx.doi.org/10.13039/501100000265;
            Award ID: G1001052
            Funded by: Wellcome Trust, DOI http://dx.doi.org/10.13039/100004440;
            Award ID: 093053/Z/10/Z
            Funded by: Bloodwise, DOI http://dx.doi.org/10.13039/501100007903;
            Award ID: 15012
            Funded by: Wellcome Trust, DOI http://dx.doi.org/10.13039/100004440;
            Award ID: 103865
            Funded by: Medical Research Council, DOI http://dx.doi.org/10.13039/501100000265;
            Award ID: J007439
            Award ID: G1001052
            Funded by: European Union Seventh Framework Program, DOI http://dx.doi.org/10.13039/100011102;
            Award ID: FP7/2007–2013
            Award ID: 317040
            Funded by: Leukemia and Lymphoma Research, DOI http://dx.doi.org/10.13039/501100000651;
            Award ID: 15012
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            Research Articles
            Brief Definitive Report
            311
            315

            Medicine

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