title: Intestinal myofibroblast-specific Tpl2-Cox-2-PGE2 pathway links innate sensing to epithelial homeostasis.
abstract: Tumor progression locus-2 (Tpl2) kinase is a major inflammatory mediator in immune cell types recently found to be genetically associated with inflammatory bowel diseases (IBDs). Here we show that Tpl2 may exert a dominant homeostatic rather than inflammatory function in the intestine mediated specifically by subepithelial intestinal myofibroblasts (IMFs). Mice with complete or IMF-specific Tpl2 ablation are highly susceptible to epithelial injury-induced colitis showing impaired compensatory proliferation in crypts and extensive ulcerations without significant changes in inflammatory responses. Following epithelial injury, IMFs sense innate or inflammatory signals and activate, via Tpl2, the cyclooxygenase-2 (Cox-2)-prostaglandin E2 (PGE2) pathway, which we show here to be essential for the epithelial homeostatic response. Exogenous PGE2 administration rescues mice with complete or IMF-specific Tpl2 ablation from defects in crypt function and susceptibility to colitis. We also show that Tpl2 expression is decreased in IMFs isolated from the inflamed ileum of IBD patients indicating that Tpl2 function in IMFs may be highly relevant to human disease. The IMF-mediated mechanism we propose also involves the IBD-associated genes IL1R1, MAPK1, and the PGE2 receptor-encoding PTGER4. Our results establish a previously unidentified myofibroblast-specific innate pathway that regulates intestinal homeostasis and may underlie IBD susceptibility in humans.
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece; kollias@fleming.gr roulis@fleming.gr.
authors.forename: Manolis
authors.initials: M
authors.lastname: Roulis
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece;
authors.forename: Christoforos
authors.initials: C
authors.lastname: Nikolaou
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece;
authors.forename: Elena
authors.initials: E
authors.lastname: Kotsaki
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece;
authors.forename: Eleanna
authors.initials: E
authors.lastname: Kaffe
authors.affiliation: Biomedcode Hellas SA, Vari 16672, Greece;
authors.forename: Niki
authors.initials: N
authors.lastname: Karagianni
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece;
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Koliaraki
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece;
authors.forename: Klelia
authors.initials: K
authors.lastname: Salpea
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece; McGill University and Genome Quebec Innovation Center, Montreal, QC, Canada H3A 0G1;
authors.forename: Jiannis
authors.initials: J
authors.lastname: Ragoussis
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece;
authors.forename: Vassilis
authors.initials: V
authors.lastname: Aidinis
authors.affiliation: Department of Medicine 1, Friedrich-Alexander-University, 91052 Erlangen, Germany;
authors.forename: Eva
authors.initials: E
authors.lastname: Martini
authors.affiliation: Department of Medicine 1, Friedrich-Alexander-University, 91052 Erlangen, Germany;
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.affiliation: David Geffen School of Medicine, University of California, Los Angeles, CA, 90095-1570; and.
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.affiliation: Inflammatory Bowel Disease Center, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Vetrano
authors.affiliation: Inflammatory Bowel Disease Center, Humanitas Clinical and Research Center, 20089 Rozzano, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.affiliation: Institute of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Vari 16672, Greece; kollias@fleming.gr roulis@fleming.gr.
authors.forename: George
authors.initials: G
authors.lastname: Kollias
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016264:Dextran Sulfate; D015232:Dinoprostone / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D004198:Disease Susceptibility; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000473:pathology; D007422:Intestines / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D058628:Myofibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011518:Proto-Oncogene Proteins; D016264:Dextran Sulfate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; C489843:Map3k8 protein, mouse; D015232:Dinoprostone
keywords: Crohn's disease; MAP kinases; cyclooxygenase-2; mesenchymal cells; ulcerative colitis