Research ArticleBARRIER DYSFUNCTION

The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses

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Science Translational Medicine  06 Jun 2018:
Vol. 10, Issue 444, eaap9736
DOI: 10.1126/scitranslmed.aap9736

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Breaching the barrier

Epithelial integrity is crucial for maintaining functionality in many bodily systems. Disruption of epithelial barriers can lead to allergies, infection, or cancer metastasis. One type of allergy, eosinophilic esophagitis, damages the esophagus and can make eating very difficult. Azouz et al. observed a decrease in the serine protease inhibitor SPINK7 in eosinophilic esophagitis patient biopsies. In vitro experiments revealed that dampening of SPINK7 allowed protease disruption of epithelial cells and inflammatory cytokine production. Treatment of SPINK7-silenced cells with a broad-spectrum antiserine protease restored homeostasis, suggesting that protease inhibitors could be helpful in eosinophilic esophagitis therapy.

Abstract

Loss of barrier integrity has an important role in eliciting type 2 immune responses, yet the molecular events that initiate and connect this with allergic inflammation remain unclear. We reveal an endogenous, homeostatic mechanism that controls barrier function and inflammatory responses in esophageal allergic inflammation. We show that a serine protease inhibitor, SPINK7 (serine peptidase inhibitor, kazal type 7), is part of the differentiation program of human esophageal epithelium and that SPINK7 depletion occurs in a human allergic, esophageal condition termed eosinophilic esophagitis. Experimental manipulation strategies reducing SPINK7 in an esophageal epithelial progenitor cell line and primary esophageal epithelial cells were sufficient to induce barrier dysfunction and transcriptional changes characterized by loss of cellular differentiation and altered gene expression known to stimulate allergic responses (for example, FLG and SPINK5). Epithelial silencing of SPINK7 promoted production of proinflammatory cytokines including thymic stromal lymphopoietin (TSLP). Loss of SPINK7 increased the activity of urokinase plasminogen-type activator (uPA), which in turn had the capacity to promote uPA receptor–dependent eosinophil activation. Treatment of epithelial cells with the broad-spectrum antiserine protease, α1 antitrypsin, reversed the pathologic features associated with SPINK7 silencing. The relevance of this pathway in vivo was supported by finding genetic epistasis between variants in TSLP and the uPA-encoding gene, PLAU. We propose that the endogenous balance between SPINK7 and its target proteases is a key checkpoint in regulating mucosal differentiation, barrier function, and inflammatory responses and that protein replacement with antiproteases may be therapeutic for select allergic diseases.

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