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Immunoproteasome impairment via β5i/LMP7-deletion leads to sustained pancreatic injury from experimental pancreatitis.


ABSTRACT: Uncovering potential new targets involved in pancreatitis may permit the development of new therapies and improvement of patient's outcome. Acute pancreatitis is a primarily sterile disease characterized by a severe systemic inflammatory response associated with extensive necrosis and a mortality rate of up to 24%. Considering that one of the reported disease mechanisms comprises the endoplasmic reticulum (ER) stress response and that the immunoproteasome is a key regulator to prevent proteotoxic stress in an inflammatory context, we investigated its role in acute pancreatitis. In this study, we demonstrate that immunoproteasome deficiency by deletion of the β5i/LMP7-subunit leads to persistent pancreatic damage. Interestingly, immunoproteasome-deficient mice unveil increased activity of pancreatic enzymes in the acute disease phase as well as higher secretion of Interleukin-6 and transcript expression of the Interleukin IL-1β, IFN-β cytokines and the CXCL-10 chemokine. Cell death was increased in immunoproteasome-deficient mice, which appears to be due to the increased accumulation of ubiquitin-protein conjugates and prolonged unfolded protein response. Accordingly, our findings suggest that the immunoproteasome plays a protective role in acute pancreatitis via its role in the clearance of damaged proteins and the balance of ER stress responses in pancreatic acini and in macrophages cytokine production.

SUBMITTER: de Freitas Chama LL 

PROVIDER: S-EPMC8278072 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Immunoproteasome impairment via β5i/LMP7-deletion leads to sustained pancreatic injury from experimental pancreatitis.

de Freitas Chama Laura L LL   Ebstein Frédéric F   Wiesrecker Birthe B   Wagh Preshit R PR   Hammer Elke E   Weiss Frank U FU   Junker Heike H   Studencka-Turski Maja M   Lerch Markus M MM   Krüger Elke E   Sendler Matthias M  

Journal of cellular and molecular medicine 20210615 14


Uncovering potential new targets involved in pancreatitis may permit the development of new therapies and improvement of patient's outcome. Acute pancreatitis is a primarily sterile disease characterized by a severe systemic inflammatory response associated with extensive necrosis and a mortality rate of up to 24%. Considering that one of the reported disease mechanisms comprises the endoplasmic reticulum (ER) stress response and that the immunoproteasome is a key regulator to prevent proteotoxi  ...[more]

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