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EMBO J. 2018 Nov 29. pii: e100101. doi: 10.15252/embj.2018100101. [Epub ahead of print]

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

Author information

1
European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy.
2
Department of Comparative Biomedicine and Food Science, University of Padova, Padova, Italy.
3
Department of Molecular Medicine, University of Padova, Padova, Italy.
4
Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
5
Department of Experimental Medicine, University of Perugia, Perugia, Italy.
6
Pediatric Unit, Department of Translational Medical Sciences, Regional Cystic Fibrosis Center, Federico II University Naples, Naples, Italy.
7
Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
8
Department of Chemical, Materials and Production Engineering, Federico II University Naples, Naples, Italy.
9
Department of Food Safety, Nutrition and Veterinary Public Health, Istituto Superiore di Sanità, Roma, Italy.
10
University San Raffaele and 21 IRCCS San Raffaele, Rome, Italy.
11
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Munich (LMU), Munich, Germany.
12
Institute of Physiology CH, University of Zurich, Zurich, Switzerland.
13
National Institute for Infectious Diseases IRCCS "L. Spallanzani", Rome, Italy.
14
Centre de Recherche des Cordeliers, Equipe11 labellisée Ligue Nationale Contrele Cancer, Paris, France kroemer@orange.fr luigi.maiuri@gmail.com.
15
Centre de Recherche des Cordeliers, INSERM U1138, Paris, France.
16
Université Paris Descartes, Paris, France.
17
Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France.
18
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
19
Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
20
European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy kroemer@orange.fr luigi.maiuri@gmail.com.

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.

KEYWORDS:

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

PMID:
30498130
DOI:
10.15252/embj.2018100101
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