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      Tissue-specific macrophages: how they develop and choreograph tissue biology

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          Abstract

          Macrophages are innate immune cells that form a 3D network in all our tissues, where they phagocytose dying cells and cell debris, immune complexes, bacteria and other waste products. Simultaneously, they produce growth factors and signalling molecules — such activities not only promote host protection in response to invading microorganisms but are also crucial for organ development and homeostasis. There is mounting evidence of macrophages orchestrating fundamental physiological processes, such as blood vessel formation, adipogenesis, metabolism and central and peripheral neuronal function. In parallel, novel methodologies have led to the characterization of tissue-specific macrophages, with distinct subpopulations of these cells showing different developmental trajectories, transcriptional programmes and life cycles. Here, we summarize our growing knowledge of macrophage diversity and how macrophage subsets orchestrate tissue development and function. We further interrelate macrophage ontogeny with their core functions across tissues, that is, the signalling events within the macrophage niche that may control organ functionality during development, homeostasis and ageing. Finally, we highlight the open questions that will need to be addressed by future studies to better understand the tissue-specific functions of distinct macrophage subsets.

          Abstract

          Macrophages are important for host immunity to infections and for clearing waste products from tissues, but they also maintain tissue health by regulating metabolism, neuronal functions and many other biological processes. Here, Elvira Mass and co-workers discuss the different tissue-specific macrophage populations that are found throughout the body, highlighting shared and unique aspects of their developmental trajectories, transcriptional programmes and physiological functions.

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          Most cited references232

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          Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage

          Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1+SiglecF+ transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologues of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury.
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            A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease.

            Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)(-/-) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.
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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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                Author and article information

                Contributors
                elvira.mass@uni-bonn.de
                Journal
                Nat Rev Immunol
                Nat Rev Immunol
                Nature Reviews. Immunology
                Nature Publishing Group UK (London )
                1474-1733
                1474-1741
                15 March 2023
                : 1-17
                Affiliations
                [1 ]GRID grid.10388.32, ISNI 0000 0001 2240 3300, Developmental Biology of the Immune System, Life and Medical Sciences (LIMES) Institute, , University of Bonn, ; Bonn, Germany
                [2 ]GRID grid.5330.5, ISNI 0000 0001 2107 3311, Division of Genetics, Department of Biology, , University of Erlangen-Nürnberg, ; Erlangen, Germany
                [3 ]GRID grid.5963.9, Institute of Neuropathology, Faculty of Medicine, , University of Freiburg, ; Freiburg, Germany
                [4 ]GRID grid.5963.9, Centre for Integrative Biological Signalling Studies, , University of Freiburg, ; Freiburg, Germany
                [5 ]GRID grid.5963.9, Centre for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, , University of Freiburg, ; Freiburg, Germany
                [6 ]GRID grid.10388.32, ISNI 0000 0001 2240 3300, Quantitative Systems Biology, Life and Medical Sciences (LIMES) Institute, , University of Bonn, ; Bonn, Germany
                Author information
                http://orcid.org/0000-0003-2318-2356
                http://orcid.org/0000-0002-5418-316X
                http://orcid.org/0000-0002-9272-4780
                Article
                848
                10.1038/s41577-023-00848-y
                10017071
                36922638
                d985eabf-163b-4d97-9ee9-d0544e58cce3
                © Springer Nature Limited 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 14 February 2023
                Categories
                Review Article

                monocytes and macrophages,myelopoiesis
                monocytes and macrophages, myelopoiesis

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