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      Teaching Old Dogs New Tricks? The Plasticity of Lung Alveolar Macrophage Subsets

      1 , 1 , *

      Trends in Immunology

      The Authors. Published by Elsevier Ltd.

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          Abstract

          Alveolar macrophages (AMs) are highly abundant lung cells with important roles in homeostasis and immunity. Their function influences the outcome of lung infections, lung cancer, and chronic inflammatory disease. Recent findings reveal functional heterogeneity of AMs. Following lung insult, resident AMs can either remain unchanged, acquire new functionality, or be replaced by monocyte-derived AMs. Evidence from mouse models correlates AM function with their embryonic or monocyte origin. We hypothesize that resident AMs are terminally differentiated cells with low responsiveness and limited plasticity, while recruited, monocyte-derived AMs are initially highly immunoreactive but more plastic, able to change their function in response to environmental cues. Understanding cell-intrinsic and -extrinsic mechanisms determining AM function may provide opportunities for intervention in lung disease.

          Highlights

          • In mice at steady state, embryonically derived tissue-resident alveolar macrophages (AMs) self-sustain over a lifetime and fulfill their homeostatic function of surfactant removal. Following various lung insults, including influenza A virus infection and bleomycin-induced lung fibrosis, these cells show only minimal transcriptional and functional changes, suggesting that resident AMs are terminally differentiated, highly specialized, and not very plastic.

          • In naïve mice, the contribution of monocyte-derived cells to AMs is negligible, but they become major components of the AM population post-lung insult. The functionality of recruited AMs can determine increased antibacterial protection, reduced asthma, and elevated lung fibrosis, depending on the specific initial insult studied.

          • When the newly recruited population of monocyte-derived AMs persist in the mouse lung, they start to resemble tissue-resident AMs, suggesting that the lung environment sends cues to shape their relatively non-inflammatory, immunosedated phenotype.

          • The high reactivity of recently recruited AMs might be best explained as a transcriptional and epigenetic legacy from their prior monocyte identity. Alternatively, training, acting through epigenetic and transcriptional reprogramming on hematopoietic stem cells or monocytes in the blood or in the lung, may imprint the high reactivity of recruited AMs.

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          Most cited references 55

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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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            Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.

            Monocyte differentiation into macrophages represents a cornerstone process for host defense. Concomitantly, immunological imprinting of either tolerance or trained immunity determines the functional fate of macrophages and susceptibility to secondary infections. We characterized the transcriptomes and epigenomes in four primary cell types: monocytes and in vitro-differentiated naïve, tolerized, and trained macrophages. Inflammatory and metabolic pathways were modulated in macrophages, including decreased inflammasome activation, and we identified pathways functionally implicated in trained immunity. β-glucan training elicits an exclusive epigenetic signature, revealing a complex network of enhancers and promoters. Analysis of transcription factor motifs in deoxyribonuclease I hypersensitive sites at cell-type-specific epigenetic loci unveiled differentiation and treatment-specific repertoires. Altogether, we provide a resource to understand the epigenetic changes that underlie innate immunity in humans. Copyright © 2014, American Association for the Advancement of Science.
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              Tissue-Resident Macrophage Ontogeny and Homeostasis.

              Defining the origins and developmental pathways of tissue-resident macrophages should help refine our understanding of the role of these cells in various disease settings and enable the design of novel macrophage-targeted therapies. In recent years the long-held belief that macrophage populations in the adult are continuously replenished by monocytes from the bone marrow (BM) has been overturned with the advent of new techniques to dissect cellular ontogeny. The new paradigm suggests that several tissue-resident macrophage populations are seeded during waves of embryonic hematopoiesis and self-maintain independently of BM contribution during adulthood. However, the exact nature of the embryonic progenitors that give rise to adult tissue-resident macrophages is still debated, and the mechanisms enabling macrophage population maintenance in the adult are undefined. Here, we review the emergence of these concepts and discuss current controversies and future directions in macrophage biology.
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                Author and article information

                Journal
                Trends Immunol
                Trends Immunol
                Trends in Immunology
                The Authors. Published by Elsevier Ltd.
                1471-4906
                1471-4981
                4 September 2020
                4 September 2020
                Affiliations
                [1 ]Immunoregulation Laboratory, Francis Crick Institute, London, UK
                Author notes
                [* ]Correspondence:
                Article
                S1471-4906(20)30185-X
                10.1016/j.it.2020.08.008
                7472979
                © 2020 The Authors

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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                Immunology

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