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Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells

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Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis This information is current as of September 29, 2021. Long Hang, Arthur M. Blum, Sangeeta Kumar, Joseph F. Urban, Jr., Makedonka Mitreva, Timothy G. Geary, Armando Jardim, Mary M. Stevenson, Clifford A. Lowell and Joel V. Weinstock J Immunol published online 24 August 2016 Downloaded from http://www.jimmunol.org/content/early/2016/08/24/jimmun ol.1600063 http://www.jimmunol.org/ Why The JI? Submit online. • 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 by guest on September 29, 2021 *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 © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 24, 2016, doi:10.4049/jimmunol.1600063 The Journal of Immunology Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis Long Hang,* Arthur M. Blum,* Sangeeta Kumar,* Joseph F. Urban, Jr.,† Makedonka Mitreva,‡ Timothy G. Geary,x Armando Jardim,x Mary M. Stevenson,{,‖ Clifford A. Lowell,# and Joel V. Weinstock* Helminthic infections modulate host immunity and may protect people in less-developed countries from developing immunological diseases. In a murine colitis model, the helminth Heligmosomoides polygyrus bakeri prevents colitis via induction of regulatory dendritic cells (DCs). The mechanism driving the development of these regulatory DCs is unexplored. There is decreased expression of the intracellular signaling pathway spleen tyrosine kinase (Syk) in intestinal DCs from H. polygyrus bakeri–infected Downloaded from mice. To explore the importance of this observation, it was shown that intestinal DCs from DC-specific Syk2/2 mice were powerful inhibitors of murine colitis, suggesting that loss of Syk was sufficient to convert these cells into their regulatory phenotype. DCs sense gut flora and damaged epithelium via expression of C-type lectin receptors, many of which signal through the Syk signaling pathway. It was observed that gut DCs express mRNA encoding for C-type lectin (CLEC) 7A, CLEC9A, CLEC12A, and CLEC4N. H. polygyrus bakeri infection downmodulated CLEC mRNA expression in these cells. Focusing on CLEC7A, which encodes for the dectin-1 receptor, flow analysis showed that H. polygyrus bakeri decreases dectin-1 expression on the intestinal DC subsets that http://www.jimmunol.org/ drive Th1/Th17 development. DCs become unresponsive to the dectin-1 agonist curdlan and fail to phosphorylate Syk after agonist stimulation. Soluble worm products can block CLEC7A and Syk mRNA expression in gut DCs from uninfected mice after a brief in vitro exposure. Thus, downmodulation of Syk expression and phosphorylation in intestinal DCs could be important mechanisms through which helminths induce regulatory DCs that limit colitis. The Journal of Immunology, 2016, 197: 000–000. any diseases caused by immune dysregulation are like inflammatory bowel disease (IBD). Several clinical and epi- frequent in developed nations but are uncommon in demiologic studies support this concept (1). M less-developed countries. Helminths are worm-like par- Animal models of colitis showed that helminths modulate in- by guest on September 29, 2021 asitic organisms that frequently infect humans in geographic re- testinal inflammation through enhancement of immune regulation. gions with low prevalence of these diseases. Helminthic infections Cells implicated in this regulation include regulatory T cells (2–4), are strong inducers of immune-regulatory circuits. This suggests macrophages (5–9) and dendritic cells (DCs) (10, 11). that loss of helminthic infections in developed countries as a result Alterations in DC function may be particularly important, as of improved sanitation and a clean food supply could be one of demonstrated in a Rag/T cell transfer model of IBD. T and B cell– the factors promoting the increase in immune-mediated diseases deficient Rag mice reconstituted with IL102/2 T cells develop colitis. Rag mice infected with Heligmosomoides polygyrus bakeri before IL102/2 T cell reconstitution are protected from the dis- *Division of Gastroenterology–Hepatology, Department of Internal Medicine, Tufts † ease (10). The mechanism underlying this protection involves Medical Center, Boston, MA 02111; Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Agricultural Research Service, United induction of regulatory DCs in the intestinal mucosa (10). Com- States Department of Agriculture, Beltsville, MD 20705; ‡Genome Institute, Wash- pared with DCs from uninfected animals, intestinal DCs isolated ington University School of Medicine, St. Louis, MO 63108; xInstitute of Parasitol- ogy, McGill University, Sainte-Anne-de-Bellevue, Quebec H9X 3V9, Canada; after H. polygyrus bakeri infection only weakly support Ag-driven {Department of Microbiology and Immunology, McGill University, Montreal, Que- IFN-g and IL-17 secretion. Furthermore, DCs isolated from the ‖ bec H3A 2B4, Canada; Department of Medicine, McGill University, Montreal, intestines of H. polygyrus bakeri–infected Rag mice transferred Quebec H4A 3J1, Canada; and #Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143 into colitis-susceptible mice block colitis (11). How these regu- ORCIDs: 0000-0002-1590-8869 (J.F.U.); 0000-0001-9572-3436 (M.M.); 0000-0002- latory DCs quell colitis is only partly characterized (11). 9619-6663 (A.J.); 0000-0002-4766-1047 (M.M.S.); 0000-0002-0467-7073 (C.A.L.). DCs are the critical link between innate and adaptive immunity. Received for publication January 11, 2016. Accepted for publication July 14, 2016. They sample intestinal luminal contents and present Ags to T cells, This work was supported by National Institutes of Health Grants DK38327 and inducing their differentiation and proliferation or perhaps rendering DK058755, the Schneider Family, and the Gilman Family. them inert (12, 13). Address correspondence and reprint requests to Dr. Joel V. Weinstock, Division of Intestinal DCs sense threats coming from the gut through display Gastroenterology–Hepatology, Tufts Medical Center, 800 Washington Street, #233, of pattern recognition receptors. These are inherited, germline- Boston, MA 02111. E-mail address: [email protected] encoded receptors that instinctively engage classes of molecules Abbreviations used in this article: CLEC, C-type lectin; CTLR, C-type lectin recep- tor; DC, dendritic cell; HES, H. polygyrus bakeri excretory/secretory product; IBD, common to many types of bacteria, fungi, viruses, helminths, or inflammatory bowel disease; LP, lamina propria; LPMC, LP mononuclear cell; MLN, host dead or dying cells. One family of such receptors is the mesenteric lymph node; RPMI, RPMI 1640 medium; rt-PCR, real-time PCR; Syk, C-type lectin receptors (CTLRs). Many groups of CTLRs also are spleen tyrosine kinase; TI, terminal ileum; WT, wild-type. called C-type lectins (CLECs), which are mostly transmembrane Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 receptors that engage their ligands to induce intracellular signaling www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600063 2 H. BAKERI INHIBITS Syk SIGNALING IN GUT DCs that alters cellular function (14). Many CLECs activate DCs via according to the instructions. The beads used to isolate CD11c+ cells from the gut recovered ∼85% of these cells at ∼95% purity, as determined by phosphorylation of the spleen tyrosine kinase (Syk) signaling hi pathway (15). FACS. The beads exhibited equal efficiency at isolating the CD11c and CD11clo subsets. In earlier experiments, microarray analysis was performed on intestinal DCs isolated from H. polygyrus bakeri–infected and rt-PCR uninfected control mice to better understand how H. polygyrus Total RNA was isolated from individual samples using Quick-RNA Mini bakeri infection affects gene expression in gut DCs. The micro- Prep (Zymo Research, Irvine, CA), as per the manufacturer’s instructions. array data suggested that H. polygyrus bakeri infection profoundly RNA quality and quantity were determined using an Agilent Bioanalyzer inhibited gene expression for nearly all of the CLECs expressed (Agilent Technologies, Santa Clara, CA). RNA was converted to cDNA using qScript cDNA SuperMix (Quanta Bioscience, Gaithersburg, MD). rt- by the intestinal DCs and Syk (15). PCR was performed using the Eco Real-Time PCR System (Illumina, San Using real-time PCR (rt-PCR), the current study confirmed the Diego, CA). GAPDH levels were used to normalize the data. TaqMan real- microarray data showing that DCs from the intestine express time primers for CLEC7A, CLEC9A, CLEC12A, CLEC4N, Syk, GAPDH, mRNA for Syk, as well as for CLEC7A, CLEC9A, CLEC12A, and HPRT, and Reg3 were obtained from Applied
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