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      Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6C hi monocyte precursors

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          Abstract

          Macrophages (mφ) are essential for intestinal homeostasis and the pathology of inflammatory bowel disease (IBD), but it is unclear whether discrete mφ populations carry out these distinct functions or if resident mφ change during inflammation. We show here that most resident mφ in resting mouse colon express very high levels of CX3CR1, are avidly phagocytic and MHCII hi, but are resistant to Toll-like receptor (TLR) stimulation, produce interleukin 10 constitutively, and express CD163 and CD206. A smaller population of CX3CR1 int cells is present in resting colon and it expands during experimental colitis. Ly6C hiCCR2 + monocytes can give rise to all mφ subsets in both healthy and inflamed colon and we show that the CX3CR1 int pool represents a continuum in which newly arrived, recently divided monocytes develop into resident CX3CR1 hi mφ. This process is arrested during experimental colitis, resulting in the accumulation of TLR-responsive pro-inflammatory mφ. Phenotypic analysis of human intestinal mφ indicates that analogous processes occur in the normal and Crohn's disease ileum. These studies show for the first time that resident and inflammatory mφ in the intestine represent alternative differentiation outcomes of the same precursor and targeting these events could offer routes for therapeutic intervention in IBD.

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          Most cited references29

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          Development of monocytes, macrophages, and dendritic cells.

          Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.
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            Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria.

            Tolerance to food antigen manifests in the absence and/or suppression of antigen-specific immune responses locally in the gut but also systemically, a phenomenon known as oral tolerance. Oral tolerance is thought to originate in the gut-draining lymph nodes, which support the generation of FoxP3(+) regulatory T (Treg) cells. Here we use several mouse models to show that Treg cells, after their generation in lymph nodes, need to home to the gut to undergo local expansion to install oral tolerance. Proliferation of Treg cells in the intestine and production of interleukin-10 by gut-resident macrophages was blunted in mice deficient in the chemokine (C-X3-C motif) receptor 1 (CX3CR1). We propose a model of stepwise oral tolerance induction comprising the generation of Treg cells in the gut-draining lymph nodes, followed by migration into the gut and subsequent expansion of Treg cells driven by intestinal macrophages. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Origin of the lamina propria dendritic cell network.

              CX(3)CR1(+) and CD103(+) dendritic cells (DCs) in intestinal lamina propria play a key role in mucosal immunity. However, the origin and the developmental pathways that regulate their differentiation in the lamina propria remain unclear. We showed that monocytes gave rise exclusively to CD103(-)CX(3)CR1(+) lamina propria DCs under the control of macrophage-colony-stimulating factor receptor (M-CSFR) and Fms-like thyrosine kinase 3 (Flt3) ligands. In contrast, common DC progenitors (CDP) and pre-DCs, which give rise to lymphoid organ DCs but not to monocytes, differentiated exclusively into CD103(+)CX(3)CR1(-) lamina propria DCs under the control of Flt3 and granulocyte-macrophage-colony-stimulating factor receptor (GM-CSFR) ligands. CD103(+)CX(3)CR1(-) DCs but not CD103(-)CX(3)CR1(+) DCs in the lamina propria constitutively expressed CCR7 and were the first DCs to transport pathogenic Salmonella from the intestinal tract to the mesenteric lymph nodes. Altogether, these results underline the diverse origin of the lamina propria DC network and identify mucosal DCs that arise from pre-DCs as key sentinels of the gut immune system.
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                Author and article information

                Journal
                Mucosal Immunol
                Mucosal Immunol
                Mucosal Immunology
                Nature Publishing Group
                1933-0219
                1935-3456
                May 2013
                19 September 2012
                : 6
                : 3
                : 498-510
                Affiliations
                [1 ]Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow , Glasgow, Scotland, UK
                [2 ]Immunology Section, BMCD14, Lund University , Lund, Sweden
                [3 ]Department of Urology, Skåne University Hospital , Malmö, Sweden
                [4 ]Department of Surgery, Skåne University Hospital , Malmö, Sweden
                [5 ]Department of Gastroenterology, Skåne University Hospital , Malmö, Sweden
                [6 ]Centre d'Immunologie de Marseille-Luminy (CIML), Aix Marseille Université, INSERM U1104, CNRS UMR7280 , Marseille, France
                [7 ]Present address: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center , Rotterdam, The Netherlands
                Author notes
                Article
                mi201289
                10.1038/mi.2012.89
                3629381
                22990622
                b2679d35-db81-475d-a72d-5ce51bd0d25f
                Copyright © 2013 Society for Mucosal Immunology

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 27 April 2012
                : 31 July 2012
                Categories
                Article

                Immunology
                Immunology

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