Role of ER Stress in the pathogenesis of Celiac Disease

Celiac disease (CD) is a complex inflammatory and auto-immune disorder triggered by the ingestion of gluten, a heterogeneous mixture of seed-storage proteins, such as gliadins, present in cereals as wheat, barley, rye and oats, in genetically predisposed individuals. The disease occurs in 1% worldwide population, and its onset has genetic, immunological and environmental components. Currently, the molecular mechanisms through which gliadin triggers the CD onset are not yet completely clear. The only treatment for the disease is represented by a gluten-free diet (GFD) which is not 100% effective and is difficult to adhere by patients. In this study, we demonstrated that gliadin stimulation induces ER stress in IEC, by using both in vitro and ex vivo models. Importantly, our results indicate that ER stress has a key role in the pathogenesis of CD. At molecular level we found that extracellular gliadin peptides interact with CXCR3 at plasma membrane level which, in turn, induce the release of IP3 through the stimulation of PLC. The interaction of IP3 with IP3R onto ER membranes results in calcium release by the ER compartment thus inducing ER stress. Of note, buffering the gliadin-induced ER stress by the chemical chaperone 4PBA completely abrogates the cytopathic effects of gliadin. Moreover, we also show that gliadin-induced ER stress is responsible for: i) CXCR3 gene expression upregulation, through CHOP; ii) TG2 gene expression upregulation, through both canonical and non-canonical activation of NF-kB; iii) altered intestinal permeability; and iv) induction and release of pro-inflammatory cytokines. Therefore, our results indicate that ER stress might represent a valuable target to design a new clinical therapeutic approach to treat CD patients.