Autophagy suppresses the pathogenic immune response to dietary antigens in cystic fibrosis

Valeria R. Villella, Speranza Esposito, Eleonora Ferrari, Romina Monzani, Antonella Tosco, Federica Rossin, Alice Castaldo, Marco Silano, Gian Luigi Marseglia, Luigina Romani, Nikolai A. Barlev, Mauro Piacentini, Valeria Raia, Guido Kroemer, Luigi Maiuri

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Abstract

Under physiological conditions, a finely tuned system of cellular adaptation allows the intestinal mucosa to maintain the gut barrier function while avoiding excessive immune responses to non-self-antigens from dietary origin or from commensal microbes. This homeostatic function is compromised in cystic fibrosis (CF) due to loss-of-function mutations in the CF transmembrane conductance regulator (CFTR). Recently, we reported that mice bearing defective CFTR are abnormally susceptible to a celiac disease-like enteropathy, in thus far that oral challenge with the gluten derivative gliadin elicits an inflammatory response. However, the mechanisms through which CFTR malfunction drives such an exaggerated response to dietary protein remains elusive. Here we demonstrate that the proteostasis regulator/transglutaminase 2 (TGM2) inhibitor cysteamine restores reduced Beclin 1 (BECN1) protein levels in mice bearing cysteamine-rescuable F508del-CFTR mutant, either in homozygosis or in compound heterozygosis with a null allele, but not in knock-out CFTR mice. When cysteamine restored BECN1 expression, autophagy was increased and gliadin-induced inflammation was reduced. The beneficial effects of cysteamine on F508del-CFTR mice were lost when these mice were backcrossed into a Becn1 haploinsufficient/autophagy-deficient background. Conversely, the transfection-enforced expression of BECN1 in human intestinal epithelial Caco-2 cells mitigated the pro-inflammatory cellular stress response elicited by the gliadin-derived P31–43 peptide. In conclusion, our data provide the proof-of-concept that autophagy stimulation may mitigate the intestinal malfunction of CF patients.

Original languageEnglish
Article number258
JournalCell Death and Disease
Volume10
Issue number4
DOIs
Publication statusPublished - Apr 1 2019

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ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Villella, V. R., Esposito, S., Ferrari, E., Monzani, R., Tosco, A., Rossin, F., Castaldo, A., Silano, M., Marseglia, G. L., Romani, L., Barlev, N. A., Piacentini, M., Raia, V., Kroemer, G., & Maiuri, L. (2019). Autophagy suppresses the pathogenic immune response to dietary antigens in cystic fibrosis. Cell Death and Disease, 10(4), [258]. https://doi.org/10.1038/s41419-019-1500-x