Increased Production of LIGHT by T Cells in Eosinophilic Esophagitis Promotes Differentiation of Esophageal Fibroblasts Toward an Inflammatory Phenotype
| Autor: | Manresa, Mario C, Chiang, Austin WT, Kurten, Richard C, Dohil, Ranjan, Brickner, Howard, Dohil, Lucas, Herro, Rana, Akuthota, Praveen, Lewis, Nathan E, Croft, Michael, Aceves, Seema S |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Tumor Necrosis Factor Ligand Superfamily Member 14 Adolescent T-Lymphocytes Cells Member 14 Clinical Sciences Food Allergies ICAM1 Immune Regulation Paediatrics and Reproductive Medicine Esophagus Clinical Research Paracrine Communication Receptors Eosinophilia Genetics Humans 2.1 Biological and endogenous factors Aetiology Child Preschool Cultured Gastroenterology & Hepatology Inflammatory and immune system Neurosciences Cell Differentiation Eosinophilic Esophagitis Fibroblasts Intercellular Adhesion Molecule-1 Fibrosis Up-Regulation Fibrogenesis Phenotype Case-Control Studies Female Inflammation Mediators Tumor Necrosis Factor Digestive Diseases Signal Transduction |
| Zdroj: | Gastroenterology, vol 159, iss 5 |
| Popis: | Background & aimsEosinophilic 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 (TGFβ1) 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.MethodsWe 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 TGFβ1 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.ResultsLIGHT 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 TGFβ1 induced transcription of genes associated with a myofibroblast phenotype. Stimulation of fibroblasts with TGFβ1 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.ConclusionsT 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. TGFβ1 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. |
| Databáze: | OpenAIRE |
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