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Aberrant IL-20 Subfamily Signaling Disrupts Epithelial Barrier Function in Eosinophilic Esophagitis

Kaymak, Tanay / TK. Aberrant IL-20 Subfamily Signaling Disrupts Epithelial Barrier Function in Eosinophilic Esophagitis. 2022, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: https://edoc.unibas.ch/90301/

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Abstract

The esophageal epithelium is the first line of defense against harmful environmental antigens. Impairment of the epithelial barrier function is associated with esophageal disorders, including eosinophilic esophagitis (EoE). Members of the interleukin (IL)-20 subfamily are essential mediators between the immune system and epithelial cells. Nonetheless, the function of the IL-20 subfamily in the esophagus is unexplored.
In this Ph.D. thesis, we aim to describe the role of the IL-20 subfamily in regulating the esophageal epithelial barrier function during EoE. Analysis of esophageal biopsies and serum samples revealed elevated IL-19, IL-20, and IL-24 levels in active EoE. Combined transcriptome and proteome analysis of patient-derived esophageal organoids indicated that IL-20 subfamily cytokines downregulate the expression of filaggrins (FLG, FLG2) and other epithelial components resulting in a disturbed barrier function. Additionally, we observed that the genetic deletion of the IL-20 receptor subunit beta (IL-20RB/IL-20R2) attenuated experimental EoE and preserved esophageal FLG2 expression in an ovalbumin (OVA)-induced EoE mouse model. Furthermore, inhibition of the mitogen-activated protein kinase (MAPK) or signal transducer and activator of transcription 3 (STAT3) pathway revealed that IL-20 subfamily-mediated epithelial barrier dysfunction depends on the MAPK rather than the STAT3 pathway. Finally, MAPK inhibitor treatment reduces eosinophil and CD45+ immune cell infiltration in the EoE mouse model. Altogether, we have identified an IL-20 subfamily-mediated mechanism of esophageal barrier impairment in the pathophysiology of EoE.
Advisors:Niess, Jan Hendrik and De Libero, Gennaro and Simon, Hans-Uwe
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Tumorimmunologie > Tumorimmunologie (De Libero)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Tumorimmunologie > Tumorimmunologie (De Libero)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Gastroenterology DBM (Niess)
UniBasel Contributors:Niess, Jan Hendrik and De Libero, Gennaro
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14868
Thesis status:Complete
Number of Pages:XIII, 121
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss148689
edoc DOI:
Last Modified:06 Dec 2022 05:30
Deposited On:05 Dec 2022 11:39

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