Autophagic/Lysosomal Dysfunctions Drive Pancreatitis

Autophagy (macroautophagy) is the principal cellular pathway for lysosome driven degradation and recycling of organelles, lipids, and long-lived proteins. Studies from our and other groups reveal that efficient autophagy and lysosomal function is critical for maintaining the pancreatic acinar cell homeostasis; whereas autophagic/lysosomal dysfunctions mediate exocrine pancreas disorders. We showed that autophagic flux is impaired in experimental models of pancreatitis, mediating acinar cell vacuolization (a long-noted but poorly understood feature of the disease) and the inappropriate/intra-acinar trypsin activity, another signature response of pancreatitis. On the other hand, recent findings in genetically altered mice revealed that pancreas-specific ablation of key autophagy mediators Atg5 or Atg7 causes severe acinar cell damage (ER and oxidative stress, accumulation of dysfunctional mitochondria, impaired protein synthesis) resulting in pancreatitis with loss of acinar tissue, persistent inflammation, fibrosis, and acinar-to-ductal metaplasia. Atg5 ablation worsens cerulein-induced pancreatitis in 2 genetic models (driven by Pdx1-Cre or Spink3-Cre). Interestingly, the effects of Atg5 ablation differ between these 2 genetic models, which likely depends on the extent and cell type of pancreatic Atg5 excision; they are also gender-dependent. We further found a key role for lysosome associated membrane proteins (LAMPs) in maintaining acinar cell homeostasis. Pancreatic levels of LAMP-1 and LAMP-2 decrease in experimental models of pancreatitis, due to their degradation mediated by cathepsin B. LAMP-2 deficient mice show decreased digestive enzymes content and dysregulated amylase secretion from acinar cells; and develop progressive spontaneous pancreatitis. Importantly, features of dysfunctional autophagy, such as acinar cell vacuolization, LAMP decrease and p62/SQSTM1 accumulation, are prominent in human pancreatitis. Remarkably, acinar cell damage leading to pancreatitis results from not only direct perturbation of autophagic/lysosomal pathways, but also alterations in various pathways which in one way or another cause impaired autophagy. Examples include genetic ablation of IKKalpha and Spink3, and inactivation of the mannose-6-phospate (M6P) pathway of hydrolase (i.e., cathepsins) delivery to the lysosomes. Mice deficient in the Gnptab gene, coding for a key enzyme in M6P pathway, show dramatic defects in pancreatic cathepsin B processing/maturation and autophagic flux, and develop spontaneous pancreatitis. Interestingly, Gnptab deficiency has no effect on liver autophagy. The recent studies uncover cellular and molecular mechanisms of autophagic/lysosomal dysfunctions in pancreas, generate novel genetic models of pancreatitis, and open new venues for elucidating the pathogenic mechanism of this disease and developing/testing therapeutic approaches.