Interferon-γ signaling in eosinophilic esophagitis has implications for epithelial barrier function and programmed cell death.

Autor:	Lal M; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Burk CM; Food Allergy Center and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA., Gautam R; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Mrozek Z; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Trachsel T; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Division of Allergy, University Children's Hospital Zurich, Zurich, Switzerland.; Division of Allergy, University Children's Hospital Basel, Basel, Switzerland., Beers J; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Carroll MC; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Morgan DM; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT); Department of Chemical Engineering, MIT, Cambridge, MA, USA., Muir AB; Divison of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania., Shreffler WG; Food Allergy Center and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Ruffner MA; Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Department of Pediatrics, Perelman School of Medicine at University of Pennsylvania.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 30. Date of Electronic Publication: 2024 Jan 30.
DOI:	10.1101/2024.01.26.577407
Abstrakt:	Objective: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory disorder characterized by eosinophil-rich mucosal inflammation and tissue remodeling. Transcriptional profiling of esophageal biopsies has previously revealed upregulation of type I and II interferon (IFN) response genes. We aim to unravel interactions between immune and epithelial cells and examine functional significance in esophageal epithelial cells. Design: We investigated epithelial gene expression from EoE patients using single-cell RNA sequencing and a confirmatory bulk RNA-sequencing experiment of isolated epithelial cells. The functional impact of interferon signaling on epithelial cells was investigated using in vitro organoid models. Results: We observe upregulation of interferon response signature genes (ISGs) in the esophageal epithelium during active EoE compared to other cell types, single-cell data, and pathway analyses, identified upregulation in ISGs in epithelial cells isolated from EoE patients. Using an esophageal organoid and air-liquid interface models, we demonstrate that IFN-γ stimulation triggered disruption of esophageal epithelial differentiation, barrier integrity, and induced apoptosis via caspase upregulation. We show that an increase in cleaved caspase-3 is seen in EoE tissue and identify interferon gamma (IFNG) expression predominantly in a cluster of majority-CD8+ T cells with high expression of CD69 and FOS . Conclusion: These findings offer insight into the interplay between immune and epithelial cells in EoE. Our data illustrate the relevance of several IFN-γ-mediated mechanisms on epithelial function in the esophagus, which have the potential to impact epithelial function during inflammatory conditions. Competing Interests: Conflict of interest: The authors have declared no conflict of interests.
Databáze:	MEDLINE
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