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      In the Wnt of Paneth Cells: Immune-Epithelial Crosstalk in Small Intestinal Crohn’s Disease

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          Abstract

          Paneth cells, specialized secretory epithelial cells of the small intestine, play a pivotal role in host defense and regulation of microbiota by producing antimicrobial peptides especially—but not only—the human α-defensin 5 (HD5) and HD6. In small intestinal Crohn’s disease (CD) which is an entity of inflammatory bowel diseases, the expression of HD5 and HD6 is specifically compromised leading to a disturbed barrier and change in the microbial community. Different genetically driven but also non-genetic defects associated with small intestinal CD affect different lines of antimicrobial Paneth cell functions. In this review, we focus on the mechanisms and the crosstalk of Paneth cells and bone marrow-derived cells and highlight recent studies about the role of the Wnt signaling pathway in this connection of ileal CD. In summary, different lines of investigations led by us but also now numerous other groups support and reconfirm the proposed classification of this disease entity as Paneth’s disease.

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          Most cited references21

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          Caspase-8 regulates TNF-alpha induced epithelial necroptosis and terminal ileitis

          Dysfunction of the intestinal epithelium is believed to result in excessive translocation of commensal bacteria into the bowel wall that drives chronic mucosal inflammation in Crohn's disease; an incurable inflammatory bowel disease in humans characterized by inflammation of the terminal ileum 1 . Beside the physical barrier established by the tight contact of cells, specialized epithelial cells such as Paneth cells and goblet cells provide innate immune defence functions by secreting mucus and antimicrobial peptides which hamper access and survival of bacteria adjacent to the epithelium 2 . Epithelial cell death is a hallmark of intestinal inflammation and has been discussed as a pathogenic mechanism driving Crohn's disease (CD) in humans 3 . However, the regulation of epithelial cell death and its role in intestinal homeostasis remains poorly understood. Here we demonstrate a critical role for caspase-8 in regulating necroptosis of intestinal epithelial cells (IEC) and terminal ileitis. Mice with a conditional deletion of caspase-8 in the intestinal epithelium (Casp8 ΔIEC) spontaneously developed inflammatory lesions in the terminal ileum and were highly susceptible to colitis. Casp8 ΔIEC mice lacked Paneth cells and showed reduced numbers of goblet cells suggesting dysregulated anti-microbial immune cell functions of the intestinal epithelium. Casp8 ΔIEC mice showed increased cell death in the Paneth cell area of small intestinal crypts. Epithelial cell death was induced by tumor necrosis factor (TNF) -α, was associated with increased expression of receptor-interacting protein 3 (RIP3) and could be inhibited upon blockade of necroptosis. Finally, we identified high levels of RIP3 in human Paneth cells and increased necroptosis in the terminal ileum of patients with Crohn's disease, suggesting a potential role of necroptosis in the pathogenesis of this disease. Taken together, our data demonstrate a critical function of caspase-8 in regulating intestinal homeostasis and in protecting IEC from TNF-α induced necroptotic cell death.
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            Wnt signalling induces maturation of Paneth cells in intestinal crypts.

            Wnt signalling, which is transduced through beta-catenin/TCF4, maintains the undifferentiated state of intestinal crypt progenitor cells. Mutational activation of the pathway initiates the adenomacarcinoma sequence. Whereas all other differentiated epithelial cells migrate from the crypt onto the villus, Paneth cells home towards the source of Wnt signals--that is, the crypt bottom. Here, we show that expression of a Paneth gene programme is critically dependent on TCF4 in embryonic intestine. Moreover, conditional deletion of the Wnt receptor Frizzled-5 abrogates expression of these genes in Paneth cells in the adult intestine. Conversely, adenomas in Apc-mutant mice and colorectal cancers in humans inappropriately express these Paneth-cell genes. These observations imply that Wnt signals in the crypt can separately drive a stem-cell/progenitor gene programme and a Paneth-cell maturation programme. In intestinal cancer, both gene programmes are activated simultaneously.
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              Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course of the disease.

              Crohn's disease is a heterogeneous disorder with both a genetic and environmental aetiology. Clinical classifications of the disease, such as the newly proposed Vienna classification, may help to define subgroups of patients suitable for studying the influence of specific genetic or environmental factors. To assess the stability over the course of the disease of its location and behaviour, as determined according to the Vienna classification. The notes of 297 Crohn's disease patients regularly followed up at our institution were carefully reviewed retrospectively. The behaviour and location of the disease according to the Vienna classification were determined at diagnosis and after 1, 3, 5, 10, 15, 20, and 25 years of follow up. The proportions of the different behaviours and locations of the disease were calculated at these time points. A statistical analysis of the evolution of these characteristics over 10 years was performed on a subgroup of 125 patients with at least 10 years of follow up. The influence of age at diagnosis on location and behaviour of the disease was assessed as well as the influence of location on the behaviour of the disease. The location of the disease remained relatively stable over the course of the disease. Although the proportion of patients who had a change in disease location became statistically significant after five years (p=0.01), over 10 years only 15.9% of patients had a change in location (p<0.001). We observed a more rapid and prominent change in disease behaviour, which was already statistically significant after one year (p=0.04). Over 10 years, 45.9% of patients had a change in disease behaviour (p<0.0001). The most prominent change was from non-stricturing non-penetrating disease to either stricturing (27.1%; p<0.0001) or penetrating (29.4%; p<0.0001) disease. Age at diagnosis had no influence on either location or behaviour of disease. Ileal Crohn's disease was more often stricturing, and colonic or ileocolonic Crohn's disease was more often penetrating: this was already the case at diagnosis and became more prominent after 10 years (p<0.05). Location of Crohn's disease, as defined by the Vienna classification, is a relatively stable phenotype which seems suitable for phenotype-genotype analyses. Behaviour of Crohn's disease according to the Vienna classification varies dramatically over the course of the disease and cannot be used in phenotype-genotype analyses. The potential influence of genes on the behaviour of Crohn's disease should be studied in subgroups of patients defined by their disease behaviour after a fixed duration of disease.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/462886
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                26 September 2017
                2017
                : 8
                : 1204
                Affiliations
                [1] 1Internal Medicine I, University Hospital Tübingen , Tübingen, Germany
                Author notes

                Edited by: Britta Siegmund, Charité Universitätsmedizin Berlin, Germany

                Reviewed by: Michael Sigal, Charité Universitätsmedizin Berlin, Germany; Olivia Isabella Coleman, Technische Universität München, Germany

                *Correspondence: Jan Wehkamp, jan.wehkamp@ 123456med.uni-tuebingen.de

                Specialty section: This article was submitted to Mucosal Immunity, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.01204
                5622939
                29018451
                93ff45eb-0b0e-405b-abaa-cfdd62314cca
                Copyright © 2017 Armbruster, Stange and Wehkamp.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 28 July 2017
                : 11 September 2017
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 33, Pages: 5, Words: 3105
                Funding
                Funded by: Deutsche Forschungsgemeinschaft 10.13039/501100001659
                Award ID: WE4336/2-3
                Funded by: European Research Council 10.13039/501100000781
                Award ID: DEFENSINSACTIVITY_310842
                Categories
                Immunology
                Mini Review

                Immunology
                paneth cell,crohn’s disease,defensins,wnt signaling,monocytes
                Immunology
                paneth cell, crohn’s disease, defensins, wnt signaling, monocytes

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