Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis
| Autor: | Garrett A. Osswald, Michael Brusilovsky, Mario A. Ynga-Durand, Ting Wen, Jeff E. Habel, Marc E. Rothenberg, Purnima Pathre, Netali Ben Baruch-Morgenstern, Pablo J. Abonia, Adina Y. Ballaban, Julie M. Caldwell, Nurit P. Azouz, Yueh-Chiang Hu, John A. Besse, Andrea M. Klingler |
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| Rok vydání: | 2020 |
| Předmět: |
Protease
business.industry medicine.medical_treatment KLK5 Epithelial Cells Eosinophilic Esophagitis General Medicine Kallikrein medicine.disease Article Pathogenesis Mice Cytokine Cancer research Animals Humans Receptor PAR-2 Medicine Eosinophilia Gene silencing Kallikreins medicine.symptom business Eosinophilic esophagitis |
| Zdroj: | Sci Transl Med |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.aaz7773 |
| Popis: | Eosinophilic esophagitis (EoE) is a chronic, food antigen–driven, inflammatory disease of the esophagus and is associated with impaired barrier function. Evidence is emerging that loss of esophageal expression of the serine peptidase inhibitor, kazal type 7 (SPINK7), is an upstream event in EoE pathogenesis. Here, we provide evidence that loss of SPINK7 mediates its pro-EoE effects via kallikrein 5 (KLK5) and its substrate, protease-activated receptor 2 (PAR2). Overexpression of KLK5 in differentiated esophageal epithelial cells recapitulated the effect of SPINK7 gene silencing, including barrier impairment and loss of desmoglein-1 expression. Conversely, KLK5 deficiency attenuated allergen-induced esophageal protease activity, modified commensal microbiome composition, and attenuated eosinophilia in a murine model of EoE. Inhibition of PAR2 blunted the cytokine production associated with loss of SPINK7 in epithelial cells and attenuated the allergen-induced esophageal eosinophilia in vivo. Clinical samples substantiated dysregulated PAR2 expression in the esophagus of patients with EoE, and delivery of the clinically approved drug α1 antitrypsin (A1AT, a protease inhibitor) inhibited experimental EoE. These findings demonstrate a role for the balance between KLK5 and protease inhibitors in the esophagus and highlight EoE as a protease-mediated disease. We suggest that antagonizing KLK5 and/or PAR2 has potential to be therapeutic for EoE. |
| Databáze: | OpenAIRE |
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