IL-20 subfamily cytokines impair the oesophageal epithelial barrier by diminishing filaggrin in eosinophilic oesophagitis.

Kaymak, Tanay; Kaya, Berna; Wuggenig, Philipp; Nuciforo, Sandro; Göldi, Andreas; Oswald, Franz; Roux, Julien; Noti, Mario; Melhem, Hassan; Hruz, Petr; Niess, Jan Hendrik (2022). IL-20 subfamily cytokines impair the oesophageal epithelial barrier by diminishing filaggrin in eosinophilic oesophagitis. (In Press). Gut BMJ Publishing Group 10.1136/gutjnl-2022-327166

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OBJECTIVE

Disruption of the epithelial barrier plays an essential role in developing eosinophilic oesophagitis (EoE), a disease defined by type 2 helper T cell (Th2)-mediated food-associated and aeroallergen-associated chronic inflammation. Although an increased expression of interleukin (IL)-20 subfamily members, IL-19, IL-20 and IL-24, in Th2-mediated diseases has been reported, their function in EoE remains unknown.

DESIGN

Combining transcriptomic, proteomic and functional analyses, we studied the importance of the IL-20 subfamily for EoE using patient-derived oesophageal three-dimensional models and an EoE mouse model.

RESULTS

Patients with active EoE have increased expression of IL-20 subfamily cytokines in the oesophagus and serum. In patient-derived oesophageal organoids stimulated with IL-20 cytokines, RNA sequencing and mass spectrometry revealed a downregulation of genes and proteins forming the cornified envelope, including filaggrins. On the contrary, abrogation of IL-20 subfamily signalling in Il20R2 -/- animals resulted in attenuated experimental EoE reflected by reduced eosinophil infiltration, lower Th2 cytokine expression and preserved expression of filaggrins in the oesophagus. Mechanistically, these observations were mediated by the mitogen-activated protein kinase (MAPK); extracellular-signal regulated kinases (ERK)1/2) pathway. Its blockade prevented epithelial barrier impairment in patient-derived air-liquid interface cultures stimulated with IL-20 cytokines and attenuated experimental EoE in mice.

CONCLUSION

Our findings reveal a previously unknown regulatory role of the IL-20 subfamily for oesophageal barrier function in the context of EoE. We propose that aberrant IL-20 subfamily signalling disturbs the oesophageal epithelial barrier integrity and promotes EoE development. Our study suggests that specific targeting of the IL-20 subfamily signalling pathway may present a novel strategy for the treatment of EoE.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Noti, Mario

ISSN:

0017-5749

Publisher:

BMJ Publishing Group

Language:

English

Submitter:

Pubmed Import

Date Deposited:

27 May 2022 07:44

Last Modified:

27 May 2022 07:53

Publisher DOI:

10.1136/gutjnl-2022-327166

PubMed ID:

35613844

Uncontrolled Keywords:

barrier function cytokines immunology oesophagitis

BORIS DOI:

10.48350/170267

URI:

https://boris.unibe.ch/id/eprint/170267

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