A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease

Valeria R. Villella, Andrea Venerando, Giorgio Cozza, Speranza Esposito, Eleonora Ferrari, Romina Monzani, Mara C. Spinella, Vasilis Oikonomou, Giorgia Renga, Antonella Tosco, Federica Rossin, Stefano Guido, Marco Silano, Enrico Garaci, Yu Kai Chao, Christian Grimm, Alessandro Luciani, Luigina Romani, Mauro Piacentini, Valeria RaiaGuido Kroemer, Luigi Maiuri

Research output: Contribution to journalArticle

Abstract

Intestinal handling of dietary proteins usually prevents local inflammatory and immune responses and promotes oral tolerance. However, in ~ 1% of the world population, gluten proteins from wheat and related cereals trigger an HLA DQ2/8-restricted TH1 immune and antibody response leading to celiac disease. Prior epithelial stress and innate immune activation are essential for breaking oral tolerance to the gluten component gliadin. How gliadin subverts host intestinal mucosal defenses remains elusive. Here, we show that the α-gliadin-derived LGQQQPFPPQQPY peptide (P31–43) inhibits the function of cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel pivotal for epithelial adaptation to cell-autonomous or environmental stress. P31–43 binds to, and reduces ATPase activity of, the nucleotide-binding domain-1 (NBD1) of CFTR, thus impairing CFTR function. This generates epithelial stress, tissue transglutaminase and inflammasome activation, NF-κB nuclear translocation and IL-15 production, that all can be prevented by potentiators of CFTR channel gating. The CFTR potentiator VX-770 attenuates gliadin-induced inflammation and promotes a tolerogenic response in gluten-sensitive mice and cells from celiac patients. Our results unveil a primordial role for CFTR as a central hub orchestrating gliadin activities and identify a novel therapeutic option for celiac disease.

Original languageEnglish
Article numbere100101
JournalEMBO Journal
DOIs
Publication statusE-pub ahead of print - Nov 29 2018

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Keywords

  • celiac disease
  • CFTR
  • gliadin
  • mucosal immunology
  • P31–43 peptide

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Villella, V. R., Venerando, A., Cozza, G., Esposito, S., Ferrari, E., Monzani, R., Spinella, M. C., Oikonomou, V., Renga, G., Tosco, A., Rossin, F., Guido, S., Silano, M., Garaci, E., Chao, Y. K., Grimm, C., Luciani, A., Romani, L., Piacentini, M., ... Maiuri, L. (2018). A pathogenic role for cystic fibrosis transmembrane conductance regulator in celiac disease. EMBO Journal, [e100101]. https://doi.org/10.15252/embj.2018100101