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

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.

CFTR is not a gluten lover either

“…The adaptive immune response causes epithelial cell stress, which promotes recruitment of invariant natural killer T (NKT) cells to the intestinal epithelium; this is believed to be a major driver of tissue destruction in CD. Here, Villella et al () discovered a new likely key cause of intestinal cell stress and destruction due to inhibition of CFTR expression and function by gliadin peptides.…”

“…Based on several similar intestinal symptoms in CD and CF, Villella et al () reasoned that aberrant intestinal CFTR function might occur in CD, and if it does, it might be corrected by CFTR potentiators. Indeed, Villella et al found that gliadin administration triggers inflammatory response in CFTR −/− mice.…”

“…This suggests competition between P31‐43 and VX‐770 (Fig ). In this respect, VX‐770 cannot activate CFTR that is already bound with P31‐43 and P31‐43 cannot inhibit CFTR that is already bound with VX‐770 (Villella et al (). By inhibiting the effects of P31‐43, VX‐770 prevented degradation of CFTR and of NHERF1, endosomal trafficking and the pathology observed in the intestinal Caco‐2 cell line treated with P31‐42.…”

“…To verify the clinical significance of their findings in cell lines and mouse models, Villella et al () used two models to examine the effect of VX‐770 on gliadin‐induced immune response in CD patients. Peripheral blood mononuclear cells (PBMCs) from CD patients in co‐culture with Caco‐2 were induced by gliadin peptides to produce IFN‐γ, which was prevented by VX‐770.…”

“…Undigested gliadin proline‐rich peptides trigger the innate and adaptive immune response, resulting in intestinal cell stress and damage. A new study by Villella et al () addressing the unclear primary cause of intestinal cell stress reports that gliadin peptides inhibit the function of the chloride and bicarbonate channel CFTR , causing intestinal cell stress, which is sufficient to trigger CD symptoms. Notably, CFTR potentiators used to treat cystic fibrosis effectively rescue CFTR function and markedly ameliorate the pathology of coeliac disease.…”