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

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 T(H)1 immune and antibody response leading to celiac...

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Detalles Bibliográficos
Autores principales: Villella, Valeria R, Venerando, Andrea, Cozza, Giorgio, Esposito, Speranza, Ferrari, Eleonora, Monzani, Romina, Spinella, Mara C, Oikonomou, Vasilis, Renga, Giorgia, Tosco, Antonella, Rossin, Federica, Guido, Stefano, Silano, Marco, Garaci, Enrico, Chao, Yu‐Kai, Grimm, Christian, Luciani, Alessandro, Romani, Luigina, Piacentini, Mauro, Raia, Valeria, Kroemer, Guido, Maiuri, Luigi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331719/
https://www.ncbi.nlm.nih.gov/pubmed/30498130
http://dx.doi.org/10.15252/embj.2018100101
Descripción
Sumario: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 T(H)1 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.