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Altered Esophageal Epithelial Differentiation in EoE and Regulation of IL-1 Cytokine Responses by Chromatin

Travers, Jared
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504802854888675

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Immunology.
The molecular and cellular etiology of eosinophilic esophagitis (EoE), an emerging tissue-specific allergic disease, involves dysregulated gene expression in esophageal epithelial cells. We assessed the expression of esophagus-specific genes in esophageal biopsy specimens from patients with EoE. We identified that 39% of esophagus-specific genes have altered expression in EoE (termed Eso-EoE genes). Notably, Eso-EoE genes are enriched for multiple IL-1 family members, proteases, and protease inhibitors. Additionally, we found dysregulated esophageal epithelial differentiation in patients with EoE. These findings demonstrated a profound loss of esophageal tissue identify in EoE and suggested that esophagus-specific, imbalanced activity of proteases and IL-1 family members is integral to the pathogenesis of EoE. We then assessed the esophageal expression of the IL-1 family member IL-33, a pro-allergic, chromatin-binding alarmin. IL-33 protein was markedly overexpressed within the nuclei of a subpopulation of basal layer esophageal epithelial cells in patients with active EoE compared to control individuals. These IL-33–positive basal epithelial cells expressed markers consistent of being undifferentiated, quiescent epithelial progenitor cells. Because strong nuclear expression of IL-33 was observed, we then aimed to uncover the characteristics and functions of the nuclear localization and chromatin binding of IL-33. Epithelial overexpression of IL-33 did not change gene expression, as assessed by RNA-sequencing. Following cellular necrosis, wild-type (WT) IL-33 demonstrated decreased extracellular release as high molecular weight species with increased intracellular retention compared to truncated IL-33. Time-lapse microscopy revealed retention of WT IL-33, but not truncated IL-33, after membrane dissolution. WT IL-33 displayed a slow, linear release over time compared with non-chromatin binding IL-33 and IL-1a. Direct interaction between released WT IL-33 and histone H2B was detected by co-immunoprecipitation. Notably, histones and IL-33 synergistically activated ST2-mediated responses. We propose that chromatin binding finely regulates the extracellular activity of IL-33 by limiting its ability to be released while simultaneously increasing both the duration of its release and ST2-mediated bioactivity. Together, our studies further our understanding of both the role of esophagus-specific genes, notably IL-1 family members, in pathogenesis of EoE and the unique regulation of the extracellular activity of IL-1 cytokines.
Marc Rothenberg, M.D. Ph.D. (Committee Chair)
George Deepe, M.D. (Committee Member)
Simon Hogan, Ph.D. (Committee Member)
Raphael Kopan, Ph.D. (Committee Member)
Susanne Wells, Ph.D. (Committee Member)
203 p.
Immunology
Allergy; Alarmin; Chromatin; Esophagus; IL-33; Inflammation

Recommended Citations

Citations

  • Travers, J. (2017). Altered Esophageal Epithelial Differentiation in EoE and Regulation of IL-1 Cytokine Responses by Chromatin [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504802854888675

    APA Style (7th edition)

  • Travers, Jared. Altered Esophageal Epithelial Differentiation in EoE and Regulation of IL-1 Cytokine Responses by Chromatin. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504802854888675.

    MLA Style (8th edition)

  • Travers, Jared. "Altered Esophageal Epithelial Differentiation in EoE and Regulation of IL-1 Cytokine Responses by Chromatin." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1504802854888675

    Chicago Manual of Style (17th edition)

ucin1504802854888675
189
© 2017, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.