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

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.

Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy

“…Autophagy also plays a fundamental role in the regulation of innate and adaptive immune responses 4 , lymphocyte differentiation, survival and homeostasis 4,5 . Several reports show the role of autophagy in the regulation of autoimmune and inflammatory pathologies including systemic lupus erythematosus, inflammatory bowel diseases, rheumatoid arthritis, psoriasis, multiple sclerosis and myositis [6][7][8][9][10][11][12][13][14][15] and hence autophagy represents potential target to treat autoimmune and inflammatory diseases 16 . Moreover, in many of these diseases, the therapeutic use of intravenous and subcutaneous immunoglobulin (IVIG/SCIG), the normal human IgG preparations obtained from the pools of plasma of several thousand healthy donors is well documented [17][18][19][20] .…”

Roles of Specialized Pro-Resolving Lipid Mediators in Autophagy and Inflammation

“…Importantly, rescuing autophagy also has beneficial effects against intestinal inflammation and dysfunction in patients with CF [139], thus extending the importance of autophagy as regulator of inflammation in multiple districts in CF.…”

Role of Cystic Fibrosis Bronchial Epithelium in Neutrophil Chemotaxis

“…Lack of autophagy in macrophages and in airway epithelial cells result in a reduced bacterial clearance and in the accumulation of dysfunctional mitochondria, which in turn promotes secretion of pro-inflammatory cytokines, indicating that autophagy may regulate the inflammation responses by suppressing the secretion of immune mediators (124)(125)(126). In fact, the rescue of dysfunctional autophagy in CF, mediated by autophagy inducers such as MTOR inhibitor (rapamycin), TG2 inhibitor (cistamine), and/or modulators of Ca 2+ -dependent signaling (KB-R7943), attenuated the hyperinflammation in CF lung, improving the CFTR transport to PM and reducing ROS production and cytokine release in macrophages and in primary CF airway cells in vitro and in CF mouse models in vivo (127)(128)(129)(130)(131)(132).…”