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Reprogramming of Monocytes by GM-CSF Contributes to Regulatory Immune Functions During Intestinal Inflammation

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Reprogramming of Monocytes by GM-CSF Contributes to Regulatory Immune Functions During Intestinal Inflammation The Journal of Immunology Reprogramming of Monocytes by GM-CSF Contributes to Regulatory Immune Functions during Intestinal Inflammation ,†,‡, ,1 ,1 Jan Da¨britz,* x Toni Weinhage,* 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 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- 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 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 M€unster, M€unster 48149, Germany; †Interdisciplinary Center of Clinical experiments; J.M.E., G.V., and J.R. gave technical support and conceptual advice; Research, University Hospital M€unster, M€unster 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 M€unster, M€unster 48149, Germany; ‖Institute of Immunology, University final version of the report and takes full responsibility for the manuscript. # Hospital M€unster, M€unster 48149, Germany; and Department of Medicine B, The sequences presented in this article have been submitted to the Gene Expres- University Hospital M€unster, M€unster 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 M€unster, Ro¨ntgen- This work was supported by the Broad Medical Research Program of the Eli and strasse 21, M€unster 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 M€unster (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 M€unster (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 M€unster (reference no. impaired clearance of bacteria from tissues (7, 8). The underlying 2006-267-f-S, obtained by Jan Da¨britz), and fully written informed consent problem appeared to be a primary immunodeficiency of macro- was obtained from all patients or legal guardians. phages, which secreted insufficient concentrations of proinflammatory DNA microarray hybridization cytokines and chemokines upon bacterial challenge (9). The view of defective macrophage functions in CD is further supported by Human monocytes were exposed to GM-CSF (10 ng/ml; MP Biomedicals, Santa Ana, CA) for 16 h or left untreated in three independent sets of an inappropriate mucosal healing (10, 11). Resolution of inflam- experiments to analyze changes in gene expression patterns induced by mation and healing relies on the infiltration of monocytes as GM-CSF. Using high-density microarrays with .22,000 oligonucleotide crucial regulators of tissue repair processes (12–14). sets, we obtained the expression levels of at least 13,000 independent Given the changing concepts on immunity and inflammation, transcripts. RNA preparation, sample preparation, and hybridization to changes in therapeutic strategies appear as a logical consequence. Affymetrix (Santa Clara, CA) Human Genome 133 A Gene Chip arrays for microarray analysis were performed as described previously (26). As a therapy that could help in overcoming insufficient macrophage functions, GM-CSF has been shown to alleviate acute dextran sulfate Statistical analysis of microarray data sodium (DSS)-induced colitis in mice (15, 16). Even more important, For analysis of data from individual donors, raw data of GM-CSF–treated it is conceivable that GM-CSF–driven modulation of innate immune samples were processed by MicroArray Suite Software (Affymetrix) using cells involved in mucosal repair and/or dampening of inflammatory data from corresponding
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