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During Intestinal Inflammation Functions Contributes to Regulatory Reprogramming of Monocytes by GM-CSF Contributes to Regulatory Immune Functions during Intestinal Inflammation This information is current as Jan Däbritz, Toni Weinhage, Georg Varga, Timo Wirth, of September 29, 2021. Karoline Walscheid, Anne Brockhausen, David Schwarzmaier, Markus Brückner, Matthias Ross, Dominik Bettenworth, Johannes Roth, Jan M. Ehrchen and Dirk Foell J Immunol 2015; 194:2424-2438; Prepublished online 4 February 2015; Downloaded from doi: 10.4049/jimmunol.1401482 http://www.jimmunol.org/content/194/5/2424 Supplementary http://www.jimmunol.org/content/suppl/2015/02/04/jimmunol.140148 http://www.jimmunol.org/ Material 2.DCSupplemental References This article cites 68 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/194/5/2424.full#ref-list-1 Why The JI? Submit online. by guest on September 29, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Reprogramming of Monocytes by GM-CSF Contributes to Regulatory Immune Functions during Intestinal Inflammation Jan Da¨britz,*,†,‡,x,1 Toni Weinhage,*,1 Georg Varga,* Timo Wirth,* Karoline Walscheid,* Anne Brockhausen,{,‖ David Schwarzmaier,* Markus Bruckner,€ # Matthias Ross,# Dominik Bettenworth,# Johannes Roth,†,‖ Jan M. Ehrchen,†,{ and Dirk Foell*,† Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF–activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to charac- terize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to Downloaded from increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell– induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-g in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn’s disease may possibly be mediated through reprogramming of monocytes to simulta- http://www.jimmunol.org/ neously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation. The Journal of Immunology, 2015, 194: 2424–2438. ur concepts of immunology have changed dramatically traditionally seen solely as effector cells of innate immunity over the past decades. The postulates of primary func- promoting host defense and driving chronic inflammation. It is O tions assigned to innate or adaptive immunity have been now accepted that monocytes can differentiate into macrophages challenged by the recognition of a complex interplay between the with various activation patterns ranging from classically activated different cellular and humoral factors that all together constitute proinflammatory to anti-inflammatory phenotypes. These cells by guest on September 29, 2021 our immune system. This helped in understanding how we are (often referred to as M1 and M2 macrophages) represent the outer protected from infections, but it also enabled discovering key margins of a broad spectrum of numerous activation and differ- aspects of autoimmunity and chronic inflammation including reg- entiation patterns of heterogeneous monocyte-derived cells (1–3). ulatory mechanisms that counteract a perpetuated immune acti- As the concepts of immunity evolve, the pathophysiology of vation. Although different functions of adaptive immune cells, chronic inflammatory diseases is also being revisited. As a striking including regulatory T cells (Tregs), are already consolidated, our example, our view of Crohn’s disease (CD) is constantly chal- understanding of different functions of innate immune cells has lenged. Traditionally, CD has been associated with a Th1 cytokine only recently been enriched. As an example, phagocytes were profile. In addition, because CD is a chronic granulomatous dis- *Department of Pediatric Rheumatology and Immunology, University Children’s J.D. and D.F. developed the concept, designed the experiments, and supervised the Hospital Munster,€ Munster€ 48149, Germany; †Interdisciplinary Center of Clinical experiments; J.M.E., G.V., and J.R. gave technical support and conceptual advice; Research, University Hospital Munster,€ Munster€ 48149, Germany; ‡Gastrointestinal M.R., G.V., and J.D. obtained ethical approval from the competent animal welfare Research in Inflammation & Pathology, Murdoch Children’s Research Institute, authorities; J.D., T. Weinhage, T. Wirth, K.W., A.B., and D.S. performed the experi- The Royal Children’s Hospital Melbourne, Parkville 3052, Victoria, Australia; ments and collected data; M.R., G.V., M.B., D.B., and T. Wirth helped with animal xDepartment of Pediatrics, University of Melbourne, Melbourne Medical School, models of experimental colitis; J.D., T. Weinhage, G.V., and D.F. analyzed the data Parkville 3052, Victoria, Australia; {Department of Dermatology, University and interpreted results; J.D. wrote the manuscript; and each author has approved the Hospital Munster,€ Munster€ 48149, Germany; ‖Institute of Immunology, University final version of the report and takes full responsibility for the manuscript. Hospital Munster,€ Munster€ 48149, Germany; and #Department of Medicine B, € € The sequences presented in this article have been submitted to the Gene Expres- University Hospital Munster, Munster 48149, Germany sion Omnibus database (http://www.ncbi.nlm.nih.gov/geo) under accession number 1J.D. and T. Weinhage contributed equally and should be considered cofirst authors. GSE63662. Received for publication June 11, 2014. Accepted for publication January 4, 2015. Address correspondence and reprint requests to Dr. Jan Da¨britz, Department of Pediatric Rheumatology and Immunology, University Children’s Hospital Munster,€ Ro¨ntgen- This work was supported by the Broad Medical Research Program of the Eli and strasse 21, Munster€ 48149, Germany. E-mail address: [email protected] Edythe Broad Foundation (Grant IBD0201 to D.F., J.D., and J.M.E.), the German Research Foundation (Grant DFG DA1161/4-1 to J.D. and D.F., Grant DFG SU195/ The online version of this article contains supplemental material. 3-2 to G.V., Grant DFG SF1009B08 to M.B.), the Innovative Medical Research € ¨ ¨ € Abbreviations used in this article: CD, Crohn’s disease; DSS, dextran sulfate sodium; Program of the University of Munster (Grants IMF DA120904 and DA3U21003 to GCsM, glucocorticoid-stimulated monocyte; GMaM, GM-CSF–activated monocyte; J.D. and D.F.), the Interdisciplinary Center for Clinical Research of the University of € LPMC, lamina propria mononuclear cell; LTB4, leukotriene B4; MEICS, murine Munster (Grant IZKF Eh2/019/11 to J.M.E.), the European Union’s Seventh Frame- endoscopic score of colitis severity; MFI, mean fluorescence intensity; MLN, mes- work Programme (Grant EC-GA305266 ‘MIAMI’ to D.F.), and a research fellowship enteric lymph node; qRT-PCR, quantitative real-time RT-PCR; ROS, reactive oxygen from the German Research Foundation (Grant DFG DA1161/5-1 to J.D.). species; Treg, regulatory T cell. Portions of this work were presented at the 50th Digestive Disease Week Annual Meeting, May 30–June 4, 2009, Chicago, IL and the 51st Digestive Disease Week Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 Annual Meeting, May 1–5, 2010, New Orleans, LA. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401482 The Journal of Immunology 2425 ease and anti-inflammatory therapies targeting innate immunity before stimulation. Monocytes from at least three different individuals have proved effective, it was a paradigm that overactive phag- were assessed with each experiment. ocytes are involved. More recently, however, emerging evidence Patients has consolidated the view of CD as a form of innate immunode- ficiency (4–6). Central to this hypothesis were the observations of Clinical and demographic characteristics of the study subjects and methods have been reported in detail previously (25). Ethical approval was obtained diminished neutrophil accumulation in patients with CD with from the Ethics Committee of the University of Munster€ (reference no. impaired clearance of bacteria from tissues (7, 8). The underlying 2006-267-f-S, obtained by Jan Da¨britz),
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