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

Maiuri et al. Italian Journal of Pediatrics (2019) 45:40 https://doi.org/10.1186/s13052-019-0627-9 COMMENTARY Open Access The gliadin-CFTR connection: new perspectives for the treatment of celiac disease Luigi Maiuri1,2ˆ , Valeria R. Villella1, Valeria Raia3 and Guido Kroemer4,5,6,7,8,9* 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. P31–43induced 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. Keywords: CFTR, Celiac disease, Gliadin Background The intestinal mucosa constitutes the first-line defense against dietary or microbial challenges and usually avoids unwarranted inflammatory reactions in response to nonself-antigens by promoting oral tolerance [1]. The capacity of the mucosal immune system to neutralize harmful luminal challenges, can be subverted by exogenous triggers, such as viruses [2], or conditions in which still undefined inherited or acquired cell-autonomous factors favor an intestinal pro-inflammatory state. Cystic fibrosis (CF), the most frequent monogenic lethal disease in the Caucasian population [3], is the quintessential example of a disease in which cell-autonomous triggers favor antigen mishandling by the intestinal mucosa. Indeed, in the CF intestine, two * Correspondence: ˆDeceased 4 Equipe11 labellisée Ligue Nationale contrele Cancer, Centre de Recherche des Cordeliers, Paris, France 5 INSERM U1138, Centre de Recherche des Cordeliers, Paris, France Full list of author information is available at the end of the article unfavorable events determine an inadequate cellular and humoral immune response to food components, (i) the increased antigenic load due to pancreatic insufficiency and (ii) the constitutive chronic intestinal inflammation due to loss-of function-mutations in the CF transmembrane conductance regulator (CFTR) gene [4, 5]. Accordingly, CF patients often manifest increased levels of antibodies against alimentary antigens, including anti-gliadin IgA antibodies, increased intestinal permeability, elevated levels of fecal calprotectin, shifts in the intestinal microbiota, and increased intestinal permeability [5–7]. Importantly, CF patients manifest a threefold increase in the prevalence of celiac disease (CD) [8, 9] a permanent intolerance to gluten/gliadin proteins that occurs in a proportion of susceptible individuals who bear the human leukocyte antigen (HLA) DQ2/ DQ8 [10–12]. Of note, a prevalence as high as ~ 4% of positive anti-TG2-IgA autoantibodies, a serological marker of CD, has been reported in several cohorts of CF patients [5–7], even in the absence of villous damage, the hallmark © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Maiuri et al. Italian Journal of Pediatrics (2019) 45:40 of CD. Thus, there is an epidemiological link between CF and CD. CF and CF, a mysterious connection The unexpected link between CF and CD, the gluten enteropathy triggered the hypothesis that CFTR might be involved in gluten sensitivity. Mounting evidence supports this hypothesis. Indeed, CFTR is not only an anion channel relevant to CF, but is also a hub protein that orchestrates the proteostasis network of epithelial cells, including enterocytes, thus regulating adaptation to cell-autonomous or external stress [13–19]. Loss of CFTR function causes increased generation of reactive oxygen species (ROS) and persistent activation of tissue transglutaminase (TGM2) [13–19], which targets several TGM2 substrates, including the autophagy-relevant Beclin 1 protein (BECN1), hence suppressing autophagy. Moreover, BECN1 targeting by TGM2 results in the functional sequestration of BECN&asssociated phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) with reduced availability of the PIK3C3 product phosphatidyl-inositol-3-phosphate (PtdIns3P) at early endosomes, thus impairing endosomal maturation and trafficking [13, 14]. In addition, TGM2 activation leads to increased nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) owing to TGM2 targeting of the NF-κB inhibitor alpha (NFKBIA) [13, 15, 18]. NF-κB activation then leads to increased levels of pro-inflam matory cytokines, including interleukin (IL)-17A, IL-21 and IL-15, a master cytokine involved in gut homeostasis [20– 22] as well as IL-1β (downstream of both NFκB and the NLRP3 inflammasome). Interestingly, these consequences of CFTR malfunction are reminiscent of those induced by some gliadin fractions in celiac intestine [12, 23, 24]. Indeed, after gluten ingestion, two major peptides, the 25-mer and the 33-mer, remain undigested and induce innate immunity activation and adaptive Th1-mediated immune responses, respectively. Some peptide fractions, such as P31–43, a fragment of to 25-mer, are capable of triggering an enterocyte stress response that is accompanied by TGM2 activation, derangement of endosomal trafficking, increased NF-κB nuclear translocation and consequent IL-15 upregulation [10, 12, 23–26]. In the intestine from CD patients, the perturbation of the local enviro (...truncated)