title: Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis.
abstract: 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 mice. To explore the importance of this observation, it was shown that intestinal DCs from DC-specific Syk(-/-) 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 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.
authors: Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111;
authors: Long
authors: L
authors: Hang
authors: Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111;
authors: Arthur M
authors: AM
authors: Blum
authors: Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111;
authors: Sangeeta
authors: S
authors: Kumar
authors: Beltsville Human Nutrition Research Center, Diet, Genomics and Immunology Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705;
authors: Joseph F
authors: 0000-0002-1590-8869
authors: JF
authors: Urban
authors: Genome Institute, Washington University School of Medicine, St. Louis, MO 63108;
authors: Makedonka
authors: 0000-0001-9572-3436
authors: M
authors: Mitreva
authors: Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, Quebec H9X 3V9, Canada;
authors: Timothy G
authors: TG
authors: Geary
authors: Institute of Parasitology, McGill University, Sainte-Anne-de-Bellevue, Quebec H9X 3V9, Canada;
authors: Armando
authors: 0000-0002-9619-6663
authors: A
authors: Jardim
authors: Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada; Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada; and.
authors: Mary M
authors: 0000-0002-4766-1047
authors: MM
authors: Stevenson
authors: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143.
authors: Clifford A
authors: 0000-0002-0467-7073
authors: CA
authors: Lowell
authors: Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA 02111; jweinstock2@tuftsmedicalcenter.org.
authors: Joel V
authors: JV
authors: Weinstock
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology / Q000469:parasitology / Q000517:prevention & control*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D007422:Intestines / Q000166:cytology* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009351:Nematospiroides dubius / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D017206:Strongylida Infections / Q000276:immunology / Q000469:parasitology; D000072377:Syk Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D000072377:Syk Kinase; C000606897:Syk protein, mouse