Functional role of kallikrein 5 and proteinase-activated receptor 2 in eosinophilic esophagitis

Nurit P. Azouz, Andrea M. Klingler, Purnima Pathre, John A. Besse, Netali Ben Baruch-Morgenstern, Adina Y. Ballaban, Garrett A. Osswald, Michael Brusilovsky, Jeff E. Habel, Julie M. Caldwell, Mario A. Ynga-Durand, Pablo J. Abonia, Yueh Chiang Hu, Ting Wen, Marc E. Rothenberg

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

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.

Original languageEnglish
Article numbereaaz7773
JournalScience Translational Medicine
Volume12
Issue number545
DOIs
StatePublished - 27 May 2020
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine

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