| First Author | Li B | Year | 2020 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1866 |
| Issue | 12 | Pages | 165971 |
| PubMed ID | 32950676 | Mgi Jnum | J:301012 |
| Mgi Id | MGI:6504173 | Doi | 10.1016/j.bbadis.2020.165971 |
| Citation | Li B, et al. (2020) Activation of alpha7nACh receptor protects against acute pancreatitis through enhancing TFEB-regulated autophagy. Biochim Biophys Acta Mol Basis Dis 1866(12):165971 |
| abstractText | Acute pancreatitis (AP) is associated with impaired acinar cell autophagic flux, intracellular zymogen activation, cell necrosis and inflammation. Activation of the cholinergic system of vagus nerve has been shown to attenuate AP, but the effect of organ-intrinsic cholinergic system on pancreatitis remains unknown. In this study, we aim to examine the effect of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) stimulation within the pancreas during AP. In vivo, AP was induced by caerulein plus LPS or ethanol plus palmitoleic acid in mice. In vitro, pancreatic acini were isolated and subjected to cholecystokinin (CCK) stimulation. Mice or acini were pre-treated with PNU-282987 (selective alpha7nAChR agonist) or methyllycaconitine citrate salt (selective alpha7nAChR antagonist). Pancreatitis severity, acinar cell injury, autophagic flux, and transcription factor EB (TFEB) pathway were analyzed. Both caerulein plus LPS in vivo and CCK in vitro led to an up-regulation of alpha7nAChR, indicating activation of pancreas-intrinsic alpha7nAChR signaling during AP. PNU-282987 decreased acinar cell injury, trypsinogen activation and pancreatitis severity. Conversely, methyllycaconitine citrate salt increased acinar cell injury and aggravated AP. Moreover, activation of alpha7nAChR by PNU-282987 promoted autophagic flux as indicated by reduced p62, increased LysoTracker staining and decreased number of autolysosomes with undegraded contents. Furthermore, PNU-282987 treatment significantly increased TFEB activity in pancreatic acinar cells. alpha7nAChR activation also attenuated pancreatic inflammation and NF-kappaB activation. Our results showed that activation of alpha7nAChR protected against experimental pancreatitis through enhancing TFEB-mediated acinar cell autophagy, suggesting that activation of pancreas-intrinsic alpha7nAChR may serve as an endogenous protective mechanism during AP. |
