Genistein antagonizes gliadin-induced CFTR malfunction in models of celiac disease

Speranza Esposito, Valeria Rachela Villella, Eleonora Ferrari, Romina Monzani, Antonella Tosco, Federica Rossin, Manuela D'Eletto, Alice Castaldo, Alessandro Luciani, Marco Silano, Gianni Bona, Gian Luigi Marseglia, Luigina Romani, Mauro Piacentini, Valeria Raia, Guido Kroemer, Luigi Maiuri

Research output: Contribution to journalArticlepeer-review

Abstract

In celiac disease (CD), an intolerance to dietary gluten/gliadin, antigenic gliadin peptides trigger an HLADQ2/ 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-transmembraneconductance- 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 gliadinsensitive mice from intestinal CFTR malfunction and gliadin-induced inflammation as it prevented gliadininduced 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.

Original languageEnglish
Pages (from-to)2003-2019
Number of pages17
JournalAging
Volume11
Issue number7
DOIs
Publication statusPublished - Apr 15 2019

Keywords

  • Celiac disease
  • CFTR
  • Genistein
  • Gluten peptides
  • Inflammation

ASJC Scopus subject areas

  • Ageing
  • Cell Biology

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