PMID- 32712105 OWN - NLM STAT- MEDLINE DCOM- 20210412 LR - 20240330 IS - 1528-0012 (Electronic) IS - 0016-5085 (Print) IS - 0016-5085 (Linking) VI - 159 IP - 5 DP - 2020 Nov TI - Increased Production of LIGHT by T Cells in Eosinophilic Esophagitis Promotes Differentiation of Esophageal Fibroblasts Toward an Inflammatory Phenotype. PG - 1778-1792.e13 LID - S0016-5085(20)34997-0 [pii] LID - 10.1053/j.gastro.2020.07.035 [doi] AB - BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is an antigen-mediated eosinophilic disease of the esophagus that involves fibroblast activation and progression to fibrostenosis. Cytokines produced by T-helper type 2 cells and transforming growth factor beta 1 (TGFbeta1) contribute to the development of EoE, but other cytokines involved in pathogenesis are unknown. We investigate the effects of tumor necrosis factor superfamily member 14 (TNFSF14, also called LIGHT) on fibroblasts in EoE. METHODS: We analyzed publicly available esophageal CD3(+) T-cell single-cell sequencing data for expression of LIGHT. Esophageal tissues were obtained from pediatric patients with EoE or control individuals and analyzed by immunostaining. Human primary esophageal fibroblasts were isolated from esophageal biopsy samples of healthy donors or patients with active EoE. Fibroblasts were cultured; incubated with TGFbeta1 and/or LIGHT; and analyzed by RNA sequencing, flow cytometry, immunoblots, immunofluorescence, or reverse transcription polymerase chain reaction. Eosinophils were purified from peripheral blood of healthy donors, incubated with interleukin 5, cocultured with fibroblasts, and analyzed by immunohistochemistry. RESULTS: LIGHT was up-regulated in the esophageal tissues from patients with EoE, compared with control individuals, and expressed by several T-cell populations, including T-helper type 2 cells. TNF receptor superfamily member 14 (TNFRSF14, also called HVEM) and lymphotoxin beta receptor are receptors for LIGHT that were expressed by fibroblasts from healthy donors or patients with active EoE. Stimulation of esophageal fibroblasts with LIGHT induced inflammatory gene transcription, whereas stimulation with TGFbeta1 induced transcription of genes associated with a myofibroblast phenotype. Stimulation of fibroblasts with TGFbeta1 increased expression of HVEM; subsequent stimulation with LIGHT resulted in their differentiation into cells that express markers of myofibroblasts and inflammatory chemokines and cytokines. Eosinophils tethered to esophageal fibroblasts after LIGHT stimulation via intercellular adhesion molecule-1. CONCLUSIONS: T cells in esophageal tissues from patients with EoE express increased levels of LIGHT compared with control individuals, which induces differentiation of fibroblasts into cells with inflammatory characteristics. TGFbeta1 increases fibroblast expression of HVEM, a receptor for LIGHT. LIGHT mediates interactions between esophageal fibroblasts and eosinophils via ICAM1. This pathway might be targeted for the treatment of EoE. CI - Copyright (c) 2020 AGA Institute. Published by Elsevier Inc. All rights reserved. FAU - Manresa, Mario C AU - Manresa MC AD - Department of Pediatrics, University of California, San Diego, San Diego; Division of Allergy Immunology; La Jolla Institute for Immunology, La Jolla, California. FAU - Chiang, Austin W T AU - Chiang AWT AD - Department of Pediatrics, University of California, San Diego, San Diego; Novo Nordisk Foundation Center for Biosustainability at the University of California, San Diego, San Diego, California. FAU - Kurten, Richard C AU - Kurten RC AD - Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, Arkansas. FAU - Dohil, Ranjan AU - Dohil R AD - Rady Children's Hospital, San Diego. FAU - Brickner, Howard AU - Brickner H AD - Department of Medicine, University of California, San Diego, San Diego, California. FAU - Dohil, Lucas AU - Dohil L AD - Department of Pediatrics, University of California, San Diego, San Diego. FAU - Herro, Rana AU - Herro R AD - Cincinnati Children's Hospital Medical Center, Immunobiology Division, Cincinnati, Ohio. FAU - Akuthota, Praveen AU - Akuthota P AD - Division of Gastroenterology, Department of Pediatrics, University of California, San Diego; Division of Pulmonary, Critical Care, and Sleep Medicine, University of California San Diego, La Jolla, California. FAU - Lewis, Nathan E AU - Lewis NE AD - Department of Pediatrics, University of California, San Diego, San Diego; Novo Nordisk Foundation Center for Biosustainability at the University of California, San Diego, San Diego, California; Department of Bioengineering, University of California, San Diego, San Diego, California. FAU - Croft, Michael AU - Croft M AD - La Jolla Institute for Immunology, La Jolla, California; Division of Gastroenterology, Department of Pediatrics, University of California, San Diego. FAU - Aceves, Seema S AU - Aceves SS AD - Department of Pediatrics, University of California, San Diego, San Diego; Division of Allergy Immunology; Rady Children's Hospital, San Diego; Division of Gastroenterology, Department of Pediatrics, University of California, San Diego. Electronic address: saceves@health.ucsd.edu. LA - eng GR - K24 AI135034/AI/NIAID NIH HHS/United States GR - R01 AI092135/AI/NIAID NIH HHS/United States GR - R01 DK114457/DK/NIDDK NIH HHS/United States GR - R35 GM119850/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200723 PL - United States TA - Gastroenterology JT - Gastroenterology JID - 0374630 RN - 0 (ICAM1 protein, human) RN - 0 (Inflammation Mediators) RN - 0 (Receptors, Tumor Necrosis Factor, Member 14) RN - 0 (TNFRSF14 protein, human) RN - 0 (TNFSF14 protein, human) RN - 0 (Tumor Necrosis Factor Ligand Superfamily Member 14) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) SB - IM MH - Adolescent MH - Case-Control Studies MH - *Cell Differentiation MH - Cells, Cultured MH - Child MH - Child, Preschool MH - Eosinophilic Esophagitis/immunology/*metabolism/pathology MH - Esophagus/immunology/*metabolism/pathology MH - Female MH - Fibroblasts/immunology/*metabolism/pathology MH - Humans MH - Inflammation Mediators/*metabolism MH - Intercellular Adhesion Molecule-1/metabolism MH - Male MH - *Paracrine Communication MH - Phenotype MH - Receptors, Tumor Necrosis Factor, Member 14/metabolism MH - Signal Transduction MH - T-Lymphocytes/immunology/*metabolism MH - Tumor Necrosis Factor Ligand Superfamily Member 14/genetics/*metabolism MH - Up-Regulation PMC - PMC7726704 MID - NIHMS1615942 OTO - NOTNLM OT - Eosinophilia OT - Fibrogenesis OT - Fibrosis OT - ICAM1 OT - Immune Regulation COIS- Conflicts of interest Ranjan Dohil and Seema S. Aceves and are co-inventors of oral viscous budesonide for eosinophilic esophagitis patented by the University of California, San Diego and licensed by Shire-Takeda. Michael Croft has patents on TNFSF14/LIGHT. Seema S. Aceves is a consultant for Regeneron, AImmune, Astellas, AstraZeneca, DBV, and Gossamer Bio. The remaining authors disclose no conflicts. EDAT- 2020/07/28 06:00 MHDA- 2021/04/13 06:00 PMCR- 2021/11/01 CRDT- 2020/07/27 06:00 PHST- 2020/01/27 00:00 [received] PHST- 2020/06/07 00:00 [revised] PHST- 2020/07/18 00:00 [accepted] PHST- 2020/07/28 06:00 [pubmed] PHST- 2021/04/13 06:00 [medline] PHST- 2020/07/27 06:00 [entrez] PHST- 2021/11/01 00:00 [pmc-release] AID - S0016-5085(20)34997-0 [pii] AID - 10.1053/j.gastro.2020.07.035 [doi] PST - ppublish SO - Gastroenterology. 2020 Nov;159(5):1778-1792.e13. doi: 10.1053/j.gastro.2020.07.035. Epub 2020 Jul 23.