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      Long-lived self-renewing bone marrow-derived macrophages displace embryo-derived cells to inhabit adult serous cavities

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          Abstract

          Peritoneal macrophages are one of the most studied macrophage populations in the body, yet the composition, developmental origin and mechanisms governing the maintenance of this compartment are controversial. Here we show resident F4/80 hiGATA6 + macrophages are long-lived, undergo non-stochastic self-renewal and retain cells of embryonic origin for at least 4 months in mice. However, Ly6C + monocytes constitutively enter the peritoneal cavity in a CCR2-dependent manner, where they mature into short-lived F4/80 loMHCII + cells that act, in part, as precursors of F4/80 hiGATA6 + macrophages. Notably, monocyte-derived F4/80 hi macrophages eventually displace the embryonic population with age in a process that is highly gender dependent and not due to proliferative exhaustion of the incumbent embryonic population, despite the greater proliferative activity of newly recruited cells. Furthermore, although monocyte-derived cells acquire key characteristics of the embryonic population, expression of Tim4 was impaired, leading to cumulative changes in the population with age.

          Abstract

          Understanding the heterogeneity of peritoneal macrophages is hampered by controversy over their origin and homeostasis. Here the authors show the embryonic F4/80hi population is replaced over time by self-renewing bone marrow-derived cells transitioning from F4/80lo to F4/80hi in adult mice, and that such turnover is more rapid in male mice.

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          Most cited references34

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          Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation.

          A defining feature of inflammation is the accumulation of innate immune cells in the tissue that are thought to be recruited from the blood. We reveal that a distinct process exists in which tissue macrophages undergo rapid in situ proliferation in order to increase population density. This inflammatory mechanism occurred during T helper 2 (T(H)2)-related pathologies under the control of the archetypal T(H)2 cytokine interleukin-4 (IL-4) and was a fundamental component of T(H)2 inflammation because exogenous IL-4 was sufficient to drive accumulation of tissue macrophages through self-renewal. Thus, expansion of innate cells necessary for pathogen control or wound repair can occur without recruitment of potentially tissue-destructive inflammatory cells.
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            Conventional and monocyte-derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell-mediated immunity to house dust mite allergen.

            Dendritic cells (DCs) are crucial for mounting allergic airway inflammation, but it is unclear which subset of DCs performs this task. By using CD64 and MAR-1 staining, we reliably separated CD11b(+) monocyte-derived DCs (moDCs) from conventional DCs (cDCs) and studied antigen uptake, migration, and presentation assays of lung and lymph node (LN) DCs in response to inhaled house dust mite (HDM). Mainly CD11b(+) cDCs but not CD103(+) cDCs induced T helper 2 (Th2) cell immunity in HDM-specific T cells in vitro and asthma in vivo. Studies in Flt3l(-/-) mice, lacking all cDCs, revealed that moDCs were also sufficient to induce Th2 cell-mediated immunity but only when high-dose HDM was given. The main function of moDCs was the production of proinflammatory chemokines and allergen presentation in the lung during challenge. Thus, we have identified migratory CD11b(+) cDCs as the principal subset inducing Th2 cell-mediated immunity in the LN, whereas moDCs orchestrate allergic inflammation in the lung. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Notch–RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen

              Signaling through Notch receptors and their transcriptional effector RBP-J is essential for lymphocyte development and function, whereas its role in other immune cell types is unclear. We tested the function of the canonical Notch–RBP-J pathway in dendritic cell (DC) development and maintenance in vivo. Genetic inactivation of RBP-J in the bone marrow did not preclude DC lineage commitment but caused the reduction of splenic DC fraction. The inactivation of RBP-J in DCs using a novel DC-specific deleter strain caused selective loss of the splenic CD8− DC subset and reduced the frequency of cytokine-secreting CD8− DCs after challenge with Toll-like receptor ligands. In contrast, other splenic DC subsets and DCs in the lymph nodes and tissues were unaffected. The RBP-J–deficient splenic CD8− DCs were depleted at the postprogenitor stage, exhibited increased apoptosis, and lost the expression of the Notch target gene Deltex1. In the spleen, CD8− DCs were found adjacent to cells expressing the Notch ligand Delta-like 1 in the marginal zone (MZ). Thus, canonical Notch–RBP-J signaling controls the maintenance of CD8− DCs in the splenic MZ, revealing an unexpected role of the Notch pathway in the innate immune system.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                13 June 2016
                2016
                : 7
                : ncomms11852
                Affiliations
                [1 ]The University of Edinburgh/MRC Centre for Inflammation Research, Queens Medical Research Institute , 47 Little France Crescent, Edinburgh EH16 4TJ, UK
                [2 ]Centre for Molecular and Cellular Biology of Inflammation (CMCBI) , New Hunt's House, King's College London, Great Maze Pond, London SE1 1UL, UK
                [3 ]Unit of Immunoregulation and Mucosal Immunology, VIB Inflammation Research Center , Ghent 9000, Belgium
                [4 ]Department of Biomedical Molecular Biology, Ghent University , Ghent 9000, Belgium
                [5 ]Institute of Infection, Immunity and Inflammation, University of Glasgow , Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, UK
                [6 ]Institute of Molecular Medicine, RWTH University , 52074 Aachen, Germany
                [7 ]Department of Internal Medicine - Nephrology University Hospital Regensburg , Regensburg 93042, Germany
                [8 ]The Roslin Institute and Royal (Dick) School of Veterinary Studies, Easter Bush Campus, University of Edinburgh , Midlothian EH25 9RG, UK
                [9 ]Immunology Program, Memorial Sloan Kettering Cancer Center , 417 East 68th Street, New York, New York 10065, USA
                [10 ]Weill Cornell Graduate School of Medical Sciences , New York, New York 10065, USA
                Author notes
                [*]

                Present address: Department of Medicine, Columbia University, 630 West 168th Street, New York, New York 10032-3784, USA.

                Author information
                http://orcid.org/0000-0003-3525-7570
                Article
                ncomms11852
                10.1038/ncomms11852
                4910019
                27292029
                2395f6e4-9376-4e89-887b-84621fd0f774
                Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 24 March 2016
                : 05 May 2016
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