Abstract
In celiac disease (CD), an intolerance to dietary gluten/gliadin, antigenic gliadin peptides trigger an HLA-DQ2/DQ8-restricted adaptive Th1 immune response. Epithelial stress, induced by other non-antigenic gliadin peptides, is required for gliadin to become fully immunogenic. We found that cystic-fibrosis-transmembrane-conductance-regulator (CFTR) acts as membrane receptor for gliadin-derived peptide P31-43, as it binds to CFTR and impairs its channel function. P31-43-induced CFTR malfunction generates epithelial stress and intestinal inflammation. Maintaining CFTR in an active open conformation by the CFTR potentiators VX-770 (Ivacaftor) or Vrx-532, prevents P31-43 binding to CFTR and controls gliadin-induced manifestations. Here, we evaluated the possibility that the over-the-counter nutraceutical genistein, known to potentiate CFTR function, would allow to control gliadin-induced alterations. We demonstrated that pre-treatment with genistein prevented P31-43-induced CFTR malfunction and an epithelial stress response in Caco-2 cells. These effects were abrogated when the CFTR gene was knocked out by CRISP/Cas9 technology, indicating that genistein protects intestinal epithelial cells by potentiating CFTR function. Notably, genistein protected gliadin-sensitive mice from intestinal CFTR malfunction and gliadin-induced inflammation as it prevented gliadin-induced IFN-γ production by celiac peripheral-blood-mononuclear-cells (PBMC) cultured ex-vivo in the presence of P31-43-challenged Caco-2 cells. Our results indicate that natural compounds capable to increase CFTR channel gating might be used for the treatment of CD.
Highlights
Celiac disease (CD), a food intolerance to dietary proteins from wheat, rye and barley, affects up to 1% of the world population [1,2,3]
Pre-incubation of Caco-2 cells with genistein controlled the P31-43 induced inflammation, secondary to transglutaminase 2 (TGM2) activation [12,13,14] (Figure 2A-2B), genistein itself had no impact on TGM2-mediated transamidation reactions (Figure 2C)
CFTR dysfunction leads to TGM2 activation and consequent autophagy inhibition, while the restoration of autophagy and the inhibition of TGM2 re-establish CFTR function at the epithelial surface [13,14,15]
Summary
Celiac disease (CD), a food intolerance to dietary proteins from wheat, rye and barley, affects up to 1% of the world population [1,2,3]. In a subset of genetically susceptible individuals bearing the human leukocyte antigen (HLA) DQ2/DQ8, the ingestion of gluten triggers an immune reaction against gluten peptide, abolishing the normal state of oral tolerance and inducing an adaptive immune response against glutenderived peptides with an autoimmune component [4,5,6]. This leads to the production of (diagnostic) autoantibodies against the self-antigen tissue transglutaminase 2 (TGM2) and eventually culminates in villous atrophy due to chronic intestinal inflammation [4,5,6,7,8]. Such “external” triggers include reovirus infections [11] and perhaps other, yet-to-bedefined factors [8] that induce epithelial stress with TGM2 activation, upregulation of IL-15 and the cytotoxic activation of intraepithelial CD8+ T lymphocytes [5,6,7,8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
