Abstract
Gliadin, the alcohol-soluble protein fraction of wheat, contains the factor toxic for celiac disease (CD), and its toxicity is not reduced by digestion with gastro-pancreatic enzymes. Importantly, it is proved that an innate immunity to gliadin plays a key role in the development of CD. The immune response induces epithelial stress and reprograms intraepithelial lymphocytes into natural killer (NK)-like cells, leading to enterocyte apoptosis and an increase in epithelium permeability. In this contribution, we have reported that in Caco-2 cells the administration of enzymatically digested gliadin (PT-gliadin) reduced significantly the expression of the autophagy-related marker LC3-II. Furthermore, electron and fluorescent microscope analysis suggested a compromised functionality of the autophagosome apparatus. The rescue of the dysregulated autophagy process, along with a reduction of PT-gliadin toxicity, was obtained with a starvation induction protocol and by 3-methyladenine administration, while rapamycin, a well-known autophagy inducer, did not produce a significant improvement in the clearance of extra- and intra-cellular fluorescent PT-gliadin amount. Altogether, our results highlighted the possible contribution of the autophagy process in the degradation and in the reduction of extra-cellular release of gliadin peptides and suggest novel molecular targets to counteract gliadin-induced toxicity in CD.
Highlights
The term “autophagy”, originally coined by De Duve [1], is a self-degradative process crucial for eukaryotic cells for balancing sources of energy during development phases and in response to different environmental conditions [2]
The effect of enzymatic digested gliadin molecules on the functionality of the autophagy process was investigated in Caco-2 cells, a widely adopted model system that resemble intestinal epithelial permeability in celiac disease (CD) studies
The results were focused on the evaluation and modulation of the autophagy process, in order to counteract gliadin cytotoxicity in Caco-2 cells
Summary
The term “autophagy”, originally coined by De Duve [1], is a self-degradative process crucial for eukaryotic cells for balancing sources of energy during development phases and in response to different environmental conditions [2]. Celiac disease (CD) is a chronic systemic autoimmune disease of the small intestine with genetic and environmental components This disease originates from a pathological immune response to ingested dietary food-derived digested gluten from different cereals like wheat, barley, and rye [11]. Several gliadin epitopes show different immunogenic and toxic properties These epitopes present multiple proline and glutamine residues that give rise to resistance to proteolysis by gastric, pancreatic, and intestinal proteases. In other CD patients, GFD was not completely effective to suppress the disease symptoms [17] In this contribution, the effect of enzymatic digested gliadin molecules on the functionality of the autophagy process was investigated in Caco-2 cells, a widely adopted model system that resemble intestinal epithelial permeability in CD studies
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