title: TRIF signaling drives homeostatic intestinal epithelial antimicrobial peptide expression.
abstract: Recent results indicate a significant contribution of innate immune signaling to maintain mucosal homeostasis, but the precise underlying signal transduction pathways are ill-defined. By comparative analysis of intestinal epithelial cells isolated from conventionally raised and germ-free mice, as well as animals deficient in the adaptor molecules MyD88 and TRIF, the TLR3 and TLR4, as well as the type I and III IFN receptors, we demonstrate significant TLR-mediated signaling under homeostatic conditions. Surprisingly, homeostatic expression of Reg3γ and Paneth cell enteric antimicrobial peptides critically relied on TRIF and, in part, TLR3 but was independent of IFN receptor signaling. Reduced antimicrobial peptide expression was associated with significantly lower numbers of Paneth cells and a reduced Paneth cell maturation and differentiation factor expression in TRIF mutant compared with wild-type epithelium. This phenotype was not transferred to TRIF-sufficient germ-free animals during cohousing. Low antimicrobial peptide expression in TRIF-deficient mice caused reduced immediate killing of orally administered bacteria but was not associated with significant alterations in the overall composition of the enteric microbiota. The phenotype was rapidly restored in a TRIF-independent fashion after transient epithelial damage. Our results identify TRIF signaling as a truly homeostatic pathway to maintain intestinal epithelial barrier function revealing fundamental differences in the innate immune signaling between mucosal homeostasis and tissue repair.
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, D-30625 Hannover, Germany; Institute of Animal Breeding and Genetics, University of Veterinary Medicine, 1210 Vienna, Austria;
authors.forename: Silvia
authors.initials: S
authors.lastname: Stockinger
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, D-30625 Hannover, Germany;
authors.forename: Claudia U
authors.initials: CU
authors.lastname: Duerr
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, D-30625 Hannover, Germany;
authors.forename: Marcus
authors.initials: M
authors.lastname: Fulde
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, D-30625 Hannover, Germany; Institute of Microbiology, Swiss Federal Institute of Technology Zürich, 8093 Zürich, Switzerland;
authors.forename: Tamas
authors.initials: T
authors.lastname: Dolowschiak
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, D-30625 Hannover, Germany;
authors.forename: Johanna
authors.initials: J
authors.lastname: Pott
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, D-30625 Hannover, Germany;
authors.forename: Ines
authors.initials: I
authors.lastname: Yang
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, D-30625 Hannover, Germany;
authors.forename: Daniel
authors.initials: D
authors.lastname: Eibach
authors.affiliation: Wallenberg Laboratory for Cardiovascular and Metabolic Research, Sahlgrenska University Hospital, University of Gothenburg, S-405 30 Gothenburg, Sweden;
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan; and.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, D-30625 Hannover, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Suerbaum
authors.affiliation: Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Brugman
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, D-30625 Hannover, Germany; hornef.mathias@mh-hannover.de.
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Hornef
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000276:immunology*; D016213:Cyclins / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D000073718:Pancreatitis-Associated Proteins; D019879:Paneth Cells / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D017471:Receptors, Interferon / Q000235:genetics; D012480:Salmonella Infections / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D023181:Antimicrobial Cationic Peptides; D016213:Cyclins; D053594:Myeloid Differentiation Factor 88; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; D017471:Receptors, Interferon; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C499078:Ccnl2 protein, mouse; C507780:Myd88 protein, mouse; C490255:Reg3g protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse