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

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.

Bioactive Compounds in Food as a Current Therapeutic Approach to Maintain a Healthy Intestinal Epithelium

“…Thus, there is a great deal of research aimed at evaluating the use of probiotics as potential treatments for FA, and preclinical studies using probiotics have investigated the mechanisms leading to the amelioration of FA outcomes. The beneficial effects of probiotics on immune balance, intestinal barrier function [ 122 ], and structure of intestinal microbiota results in an effective alleviation of allergic responses [ 123 , 124 , 125 ]. Thus, germ-free mice administered with a mixture of three probiotic strains ( L. rhamnosus LOCK0900, L. rhamnosus LOCK0908, and Lactobacillus casei LOCK0919; isolated from stool samples from healthy infants) demonstrated stronger apical junctional complexes and adherent junctions in their enterocytes that resembled those of conventional mice and expressed higher levels of ZO-1 and occludin proteins than control germ-free mice [ 123 ].…”

“…Likewise, a recent study about the effect of three lactobacillus strains ( L. plantarum ZDY2013, L. plantarum WLPL04, and L. rhamnosus GG) on the intestinal barrier function of mice with FA showed an enhancement of TJ mRNA expression that was associated with the attenuation of allergic immune response and symptom severity [ 124 ]. In ZDY2013-treated animals, species in the families Ruminococcaceae and Lachnospiraceae were less abundant; two families that were previously reported significantly increased in the gut of infants allergic to cow’s milk [ 125 ].…”

“…In vitro assays confirmed that curcumin was able to inhibit the phosphorylation of the p65 subunit of NF-κB in bone marrow-derived MCs [ 124 ]. In addition, curcumin was recently reported to inhibit the catalytic activity of the protein disulfide isomerase, which is extracellularly expressed on the surface of MCs and participates in their activation and degranulation during FA, decreasing the production of TNF-α, IL-4, IL-6, and IL-13 by MCs in response to allergens [ 125 ].…”

Cross-Linking Cellular Prion Protein Induces Neuronal Type 2-Like Hypersensitivity

“…PDIA3 identified following from DAT of MPN was found to be directly interacting with PRDX1 (found in both DAT of MPN and DMT of neuroblastoma cells), ACTB (found in DAT of MPN and both in DAT and DMT of neuroblastoma cells), and HSPD1. Recently, Krajewski and co-workers showed that protein disulfide isomerase catalytic activity plays an important role in the regulation of mast cell activation (115). They also showed that the inhibition of protein disulfide isomerase activity via pretreatment of mast cells with curcumin or other protein disulfide isomerase inhibitor such as PACMA-31 are able to supress the IgE mediated activation and various cytokines secretion (115).…”

“…Recently, Krajewski and co-workers showed that protein disulfide isomerase catalytic activity plays an important role in the regulation of mast cell activation (115). They also showed that the inhibition of protein disulfide isomerase activity via pretreatment of mast cells with curcumin or other protein disulfide isomerase inhibitor such as PACMA-31 are able to supress the IgE mediated activation and various cytokines secretion (115). Inouue et al showed that PRDX1 protects against allergenrelated hyperresponsiveness and Th2-type airway inflammation and involved in the inhibition of allergen-specific T-cell proliferation through immunological synapse (63).…”