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Protease perturbation
Universally effective and durable treatments for eosinophilic esophagitis (EoE), a disease driven by an immune reaction to food, are lacking. Previous work demonstrated that epithelial barrier disruption in EoE involves diminished expression of serine peptidase inhibitor Kazal type 7, and Azouz et al. now examine downstream players for potential therapeutic targets. Work in vitro, in vivo, and with patient samples showed that kallikrein 5 (KLK5) and its substrate protease-activated receptor 2 (PAR2) are key components of this pathway, which was also confirmed in a mouse model of EoE. Protease inhibitors protected against disease in the mouse model. Collectively, these findings suggest that restraining protease activity could restore balance and bring relief to patients with EoE.
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.
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