The gliadin-CFTR connection: new perspectives for the treatment of celiac disease

Abstract

Familial loss-of-function mutations of the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) channel protein cause cystic fibrosis (CF), the most frequent inherited life-threatening disease in the Caucasian population. A recent study indicates that the gluten/gliadin-derived peptide (P31–43) can cause CFTR inhibition in intestinal epithelial cells, thus causing a local stress response that contributes to the immunopathology of celiac disease (CD). Accordingly, an increased prevalence of CD has been observed in several cohorts of CF patients. CD is characterized by a permanent intolerance to gluten/gliadin proteins occurring in a proportion of susceptible individuals who bear the human leukocyte antigen (HLA) DQ2/DQ8. In CD, perturbations of the intestinal environment, together with the activation of the innate immune system by P31–43, are essential for rendering other immunodominant gliadin peptide fully antigenic, thus triggering an adaptive immune response with an autoimmune component. P31–43-induced CFTR inhibition elicits the danger signals that ignite the epithelial stress response and perturb epithelial proteostasis. Importantly, potentiators of CFTR channel gating, such as the FDA-approved drug Ivacaftor, prevent P31–43 driven CFTR inhibition and suppress the gliadin-induced stress response in cells from celiac patients, as well as the immunopathology developing in gliadin-sensitive mice. Thus, CFTR potentiators may represent a novel therapeutic option for celiac patients.

Cystic fibrosis transmembrane conductance regulator (CFTR) and autophagy: hereditary defects in cystic fibrosis versus gluten-mediated inhibition in celiac disease

“…In conclusion, CFTR can be inhibited in two apparently different diseases, in CF, where CFTR is mutated, and in CD, where CFTR is inhibited by gluten/gliadin-derived peptides [59] (Figure 1). In both conditions, CFTR inhibition ultimately compromises autophagy, thus reducing the capacity of cells to withstand stress and maintain tissue homeostasis.…”

Probiotics Supplements Reduce ER Stress and Gut Inflammation Associated with Gliadin Intake in a Mouse Model of Gluten Sensitivity

“…ODs (optical densities) were analyzed by a SPARK Multimode Microplate Reader (TECAN). Values were normalized to total protein concentration evaluated by Bradford analysis, as previously reported [ 10 ].…”

“…Moreover, active TG2 leads to NF- κ B activation, causing an increased level of proinflammatory cytokines such as IL-15, IL-17A, and IL-21, the main cytokines involved in CD pathogenesis. Importantly, gliadin binds to the NBD1 domain of CFTR, thus inhibiting its gating functions and impairing autophagy and proteostasis [ 6 , 10 ]. To close this vicious circle, inhibited CFTR sustains, in turn, the activity of TG2, which enhances the amount of deamidated gliadin, finally raising its antigenicity [ 10 ].…”

Probiotics Supplements Reduce ER Stress and Gut Inflammation Associated With Gliadin Intake in Celiac Disease Mouse Model

“…Moreover, active TG2 leads to NF-κB activation then causing an increased level of pro-inflammatory cytokines such as IL-15, IL-17A and IL-21, the main cytokines involved in CD pathogenesis. Importantly, gliadin binds to the NBD1 domain of CFTR thus inhibits its gating functions, impairs autophagy and proteostasis [6,10]. To close this vicious circle, inhibited CFTR sustains, in turn, the activity of TG2 which enhances the amount of deamidated gliadin, finally raising its antigenicity [10].…”

“…Importantly, gliadin binds to the NBD1 domain of CFTR thus inhibits its gating functions, impairs autophagy and proteostasis [6,10]. To close this vicious circle, inhibited CFTR sustains, in turn, the activity of TG2 which enhances the amount of deamidated gliadin, finally raising its antigenicity [10]. Importantly, the above-mentioned activation of TG2 seems to rely on gliadin-stimulated intracellular calcium mobilization from the Endoplasmic Reticulum, a condition potentially resulting in imbalanced ER homeostasis known as ER Stress [11], as evidenced in vitro by Caputo and colleagues [12].…”