title: A Novel Role for TL1A/DR3 in Protection against Intestinal Injury and Infection.
abstract: TNF-like cytokine 1A (TL1A) is expressed on APCs and provides costimulatory signals to activated lymphocytes that bear its functional receptor, death receptor 3 (DR3). TL1A/DR3 signaling is involved in the pathogenesis of human and experimental inflammatory bowel disease. In the current study, we investigated the role of this cytokine/receptor pair in acute intestinal injury/repair pathways. We demonstrate that intact DR3 signaling protected mice from acute dextran sodium sulfate colitis because DR3(-/-) mice showed more severe mucosal inflammation and increased mortality. DR3(-/-) mice were compromised in their ability to maintain adequate numbers of CD4(+)CD25(+)Foxp3(+) regulatory T cells in response to acute mucosal damage. This defect in immune regulation led to a nonspecific upregulation of effector proinflammatory pathways, which was most prominent for the Th17 immunophenotype. TL1A(-/-) mice were similarly more susceptible to dextran sodium sulfate colitis, although without mortality and with delayed kinetics compared with DR3(-/-) mice, and also displayed significantly reduced numbers of regulatory T cells. Infection of DR3(-/-) mice with Salmonella typhimurium was associated with defective microbial clearance and elevated bacterial load. Taken together, our findings indicate a novel protective role for the TL1A/DR3 axis in the regulation of mucosal homeostasis during acute intestinal injury/repair, which contrasts with its known pathogenic function during chronic intestinal inflammation.
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
authors.forename: Li-Guo
authors.initials: LG
authors.lastname: Jia
authors.affiliation: Academic Department of Gastroenterology, Kapodistrian University of Athens, Laikon Hospital, 11527 Athens, Greece;
authors.forename: Giorgos
authors.initials: G
authors.lastname: Bamias
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
authors.forename: Kristen O
authors.initials: KO
authors.lastname: Arseneau
authors.affiliation: Department of Immunobiology and Drug Discovery, Biogen Idec, Cambridge, MA 02142;
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: Department of Medical Microbiology and Infectious Diseases, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; and.
authors.forename: Eddy C Y
authors.identifier: 0000-0002-2243-4964
authors.initials: EC
authors.lastname: Wang
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106;
authors.forename: Dennis
authors.identifier: 0000-0002-5169-5100
authors.initials: D
authors.lastname: Gruszka
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106.
authors.forename: Theresa T
authors.initials: TT
authors.lastname: Pizarro
authors.affiliation: Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106; fabio.cominelli@uhhospitals.org.
authors.forename: Fabio
authors.identifier: 0000-0002-1571-1548
authors.initials: F
authors.lastname: Cominelli
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology*; D016264:Dextran Sulfate; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007422:Intestines / Q000382:microbiology / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics / Q000378:metabolism*; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000235:genetics / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse; C505947:Tnfsf15 protein, mouse; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D016264:Dextran Sulfate