Protein Disulfide Isomerases Regulate IgE-Mediated Mast Cell Responses and Their Inhibition Confers Protective Effects During Food Allergy.

Dylan Krajewski,Edwin Kaczenski,Clinton B Mathias,Megan Pantos,Stephanie H Polukort,Nickul N Shah,Justine Gelzinis,Daniel R Kennedy,Christine Galinski,Sallie S Schneider,Jeffrey Rovatti

doi:10.3389/fimmu.2020.606837

Abstract

The thiol isomerase, protein disulfide isomerase (PDI), plays important intracellular roles during protein folding, maintaining cellular function and viability. Recent studies suggest novel roles for extracellular cell surface PDI in enhancing cellular activation and promoting their function. Moreover, a number of food-derived substances have been shown to regulate cellular PDI activity and alter disease progression. We hypothesized that PDI may have similar roles during mast cell-mediated allergic responses and examined its effects on IgE-induced mast cell activity during cell culture and food allergy. Mast cells were activated via IgE and antigen and the effects of PDI inhibition on mast cell activation were assessed. The effects of PDI blockade in vivo were examined by treating mice with the irreversible PDI inhibitor, PACMA-31, in an ovalbumin-induced model of food allergy. The role of dietary PDI modulators was investigated using various dietary compounds including curcumin and quercetin-3-rutinoside (rutin). PDI expression was observed on resting mast cell surfaces, intracellularly, and in the intestines of allergic mice. Furthermore, enhanced secretion of extracellular PDI was observed on mast cell membranes during IgE and antigen activation. Insulin turbidimetric assays demonstrated that curcumin is a potent PDI inhibitor and pre-treatment of mast cells with curcumin or established PDI inhibitors such as bacitracin, rutin or PACMA-31, resulted in the suppression of IgE-mediated activation and the secretion of various cytokines. This was accompanied by decreased mast cell proliferation, FcεRI expression, and mast cell degranulation. Similarly, treatment of allergic BALB/c mice with PACMA-31 attenuated the development of food allergy resulting in decreased allergic diarrhea, mast cell activation, and fewer intestinal mast cells. The production of TH2-specific cytokines was also suppressed. Our observations suggest that PDI catalytic activity is essential in the regulation of mast cell activation, and that its blockade may benefit patients with allergic inflammation.

Highlights

IgE-mediated mast cell activation is a critical component in the induction of allergic responses to food-derived antigens [1,2,3]
We have previously demonstrated that food-derived substances such as curcumin can modulate mast cell responses during food allergy by suppressing their activation and pro-allergic effects [4]
The proper folding and assembly of proteins catalyzed by PDI as well as their dimerization is a critical component of cellular function, suggesting that the modulation of mast cell responses during allergic inflammation may depend on cell-specific regulation of PDI activity

Summary

Introduction

IgE-mediated mast cell activation is a critical component in the induction of allergic responses to food-derived antigens [1,2,3]. The cross-linking of food-specific antigens by IgE-bearing mast cells in the intestinal tract induces a stepwise cascade of activation-induced events, resulting first in the release of various pre-formed mediators from mast cell granules, followed by the synthesis of several de novo substances including various cytokines and lipid mediators. These events are tightly orchestrated involving several phosphorylative reactions that culminate in the activation of transcription factors which regulate gene expression. While some studies have demonstrated curcumin acts upon various transcription factors to regulate the expression of enzymes and cytokines [4, 11], other studies suggest that curcumin exerts these effects by modulating the redox status of the target cell [12]

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Conclusion