title: TIR-domain-containing adapter-inducing interferon-β (TRIF) regulates Th17-mediated intestinal immunopathology in colitis.
abstract: Gastrointestinal mucosa reserves abundant Th17 cells where host response to commensal bacteria maintains Th17-cell generation. Although functional heterogeneity and dynamic plasticity of Th17 cells appear to be involved in chronic inflammatory disorders, how their plasticity is regulated in intestinal mucosa is unknown. Here we show that innate TRIF signaling regulates intestinal Th17-cell generation and plasticity during colitis. Absence of TRIF in mice resulted in increased severity of experimental colitis, which was associated with aberrant generation of Th17 cells especially of interferon (IFN)-γ-expressing Th17 cells in the lamina propria. The abnormal generation and plasticity of Th17 cells involved impaired expression of interleukin (IL)-27p28 by lamina propria macrophages but not dendritic cells. Treatment of TRIF-deficient mice with IL-27p28 during colitis reduced the number and IFN-γ expression of Th17 cells in the intestine. In vitro, TRIF-deficient macrophages induced more Th17 cells than wild-type (WT) macrophages during co-culture with WT naive T cells in response to cecal bacterial antigen. Many of Th17 cells induced by TRIF-deficient macrophages expressed IFN-γ due to impaired expression of IL-27p28 by macrophages and defective activation of STAT1 in T cells. These results outline TRIF-dependent regulatory mechanism by which host response to intestinal bacteria maintains Th17-cell-mediated pathology during colitis.
authors: 1] Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA [2] Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors: S
authors: S
authors: Kanagavelu
authors: Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors: C
authors: C
authors: Flores
authors: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: J M
authors: JM
authors: Termini
authors: Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: R
authors: R
authors: Riveron
authors: Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: L
authors: L
authors: Romero
authors: Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: K
authors: K
authors: Chung
authors: Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: J
authors: J
authors: Ruiz
authors: Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: J
authors: J
authors: Hyun
authors: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: X
authors: X
authors: Yuan
authors: Division of Infectious Diseases and Immunology, Department of Biomedical Science, Medicine and Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors: J
authors: J
authors: Dagvadorj
authors: 1] Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA [2] Division of Gastroenterology, Department of Medicine, F. Widjaja Foundation, Inflammatory Bowel and Immunology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA [3] Department of Cell Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
authors: M
authors: M
authors: Fukata
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D003092:Colitis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D064094:Interleukin-27 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012720:Severity of Illness Index; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D007371:Interferon-gamma; D064094:Interleukin-27; D050794:STAT1 Transcription Factor; C476286:Ticam1 protein, mouse