Abstract
Although aberrations of intracellular vesicle transport systems towards lysosomes including autophagy and endocytosis are involved in the onset and progression of acute pancreatitis, the molecular mechanisms underlying such aberrations remain unclear. The pathways of autophagy and endocytosis are closely related, and Rab7 plays crucial roles in both. In this study, we analyzed the function of Rab7 in acute pancreatitis using pancreas-specific Rab7 knockout (Rab7Δpan) mice. In Rab7Δpan pancreatic acinar cells, the maturation steps of both endosomes and autophagosomes were deteriorated, and the lysosomal functions were affected. In experimental models of acute pancreatitis, the histopathological severity, serum amylase concentration and intra-pancreatic trypsin activity were significantly higher in Rab7Δpan mice than in wild-type mice. Furthermore, the autophagy process was blocked in Rab7Δpan pancreas compared with wild-type mice. In addition, larger autophagic vacuoles that colocalize with early endosome antigen 1 (EEA1) but not with lysosomal-associated membrane protein (LAMP)-1 were much more frequently formed in Rab7Δpan pancreatic acinar cells. Accordingly, Rab7 deficiency exacerbates the severity of acute pancreatitis by impairing the autophagic and endocytic pathways toward lysosomes.
Highlights
Organization of Occupational Health and Safety, Kanagawa, Japan
Aberration of lysosomal morphology and the expression of lysosomal-associated membrane protein (LAMP)-1 in Rab7Δpan pancreas. Because both autophagy and endocytosis are driven towards lysosomes and Rab[7] has been shown to participate in lysosome biogenesis[14], we examined lysosomal morphology and the expression of LAMP-1, which is essential for the lysosomal functions[22]
As we found that autophagy, endocytosis, and the lysosomal functions were impaired in pancreatic acinar cells of Rab7Δpan mice, we investigated the effect of Rab[7] deficiency on acute pancreatitis using experimental models of acute pancreatitis induced by caerulein or L-arginine
Summary
Organization of Occupational Health and Safety, Kanagawa, Japan. Kenichi Takahashi and Hirosato Mashima contributed to this work. Late endosomes fuse to autophagosomes during their maturation[7] Both processes require lysosomal fusion at their final steps. Vacuole formation and trypsin activation in pancreatic acinar cells during acute pancreatitis are presumed to be tightly related to autophagy and lysosomal enzymes[8]. It has been recently shown that endocytosis in pancreatic acinar cells is involved in the onset of acute pancreatitis[9]. Rab proteins belongs to the Ras-related GTP-binding protein family and function in various intracellular vesicle trafficking systems including autophagy and endocytosis[6, 13]. We and others have reported that multiple Rab proteins function in diverse vesicle trafficking systems in pancreatic acinar cells[16,17,18,19]. To elucidate the molecular mechanism underlying the participation of autophagy and endocytosis towards lysosomes in the pathophysiology of acute pancreatitis, we investigated the role of Rab[7] in several physiological conditions and acute pancreatitis using pancreas-specific Rab7-deficient mice
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