RIP3 attenuates the pancreatic damage induced by deletion of ATG7
Xiaodong Zhou1,2,3, Li Xie1,2,3, Leizhou Xia1,2,3
1Department of General, Visceral and Transplantation Surgery, University Clinic Heidelberg, Germany.
Abstract:
Invalidation of pancreatic autophagy entails pancreatic atrophy, endocrine and exocrine insufficiency and pancreatitis. The aim of this study was to investigate whether depletion of Rip3, which is involved in necroptotic signaling, may attenuate the pancreatic atrophy and pancreatitis resulting from autophagy inhibition. Autophagy and necroptosis signaling were evaluated in mice lacking expression of Rip3 in all organs and Atg7 in the pancreas. Acinar cell death, inflammation and fibrosis were evaluated by using of a compendium of immunofluorescence methods and immunoblots. Mice deficient for pancreatic Atg7 developed acute pancreatitis, which progressed to chronic pancreatitis. This phenotype reduces autophagy, increase apoptosis and necroptosis, inflammation and fibrosis, as well as premature death of the animals. Knockout of Rip3 exacerbated the apoptotic death of acinar cells, increased tissue damage, reduced macrophage infiltration and further accelerated the death of the mice with Atg7-deficient pancreas. The pancreatic degeneration induced by autophagy inhibition was exacerbated by Rip3 deletion.
Insights
Pancreatic autophagy inhibition causes pancreatitis and atrophy. Deleting Rip3, a protein in necroptosis, worsened these effects, indicating Rip3 is not protective against autophagy-impaired pancreatic damage.
Area of Science:
- Cell Biology
- Molecular Biology
- Pathology
Background:
- Pancreatic autophagy is crucial for maintaining organ homeostasis.
- Disrupting autophagy leads to pancreatic atrophy, insufficiency, and pancreatitis.
- Rip3 is implicated in necroptotic signaling pathways.
Purpose of the Study:
- To investigate if Rip3 depletion mitigates pancreatic atrophy and pancreatitis caused by autophagy inhibition.
- To elucidate the role of Rip3 in the context of impaired pancreatic autophagy.
Main Methods:
- Utilized knockout mouse models lacking Rip3 and Atg7 (in the pancreas).
- Assessed autophagy and necroptosis signaling pathways.
- Evaluated acinar cell death, inflammation, and fibrosis using immunofluorescence and immunoblots.
Main Results:
- Mice with Atg7-deficient pancreas developed acute pancreatitis progressing to chronic pancreatitis, characterized by reduced autophagy, increased apoptosis and necroptosis, inflammation, fibrosis, and premature death.
- Rip3 knockout in these mice exacerbated acinar cell apoptosis and tissue damage.
- Rip3 deletion reduced macrophage infiltration and accelerated mortality.
Conclusions:
- Rip3 deletion exacerbates pancreatic degeneration induced by autophagy inhibition.
- Rip3 is not protective and its absence worsens the pathological consequences of impaired pancreatic autophagy.
- These findings highlight the complex interplay between autophagy, apoptosis, and necroptosis in pancreatic disease.
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