Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_CE4715907BDD
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Dysfunctional autophagy following exposure to pro-inflammatory cytokines contributes to pancreatic β-cell apoptosis.
Journal
Cell death & disease
Author(s)
Lambelet M., Terra L.F., Fukaya M., Meyerovich K., Labriola L., Cardozo A.K., Allagnat F.
ISSN
2041-4889 (Electronic)
Publication state
Published
Issued date
24/01/2018
Peer-reviewed
Oui
Volume
9
Number
2
Pages
96
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Type 1 diabetes (T1D) results from β-cell destruction due to concerted action of both innate and adaptive immune responses. Pro-inflammatory cytokines, such as interleukin-1β and interferon-γ, secreted by the immune cells invading islets of Langerhans, contribute to pancreatic β-cell death in T1D. Cytokine-induced endoplasmic reticulum (ER) stress plays a central role in β-cell demise. ER stress can modulate autophagic response; however, no study addressed the regulation of autophagy during the pathophysiology of T1D. In this study, we document that cytokines activate the AMPK-ULK-1 pathway while inhibiting mTORC1, which stimulates autophagy activity in an ER stress-dependent manner. On the other hand, time-course analysis of LC3-II accumulation in autophagosomes revealed that cytokines block the autophagy flux in an ER stress independent manner, leading to the formation of large dysfunctional autophagosomes and worsening of ER stress. Cytokines rapidly impair lysosome function, leading to lysosome membrane permeabilization, Cathepsin B leakage and lysosomal cell death. Blocking cathepsin activity partially protects against cytokine-induced or torin1-induced apoptosis, whereas blocking autophagy aggravates cytokine-induced CHOP overexpression and β-cell apoptosis. In conclusion, cytokines stimulate the early steps of autophagy while blocking the autophagic flux, which aggravate ER stress and trigger lysosomal cell death. Restoration of autophagy/lysosomal function may represent a novel strategy to improve β-cell resistance in the context of T1D.
Keywords
Animals, Apoptosis, Autophagosomes/drug effects, Autophagosomes/metabolism, Autophagosomes/ultrastructure, Autophagy, Cathepsin B/metabolism, Cell Line, Cell Survival/drug effects, Cytokines/toxicity, Endoplasmic Reticulum Stress/drug effects, Humans, Inflammation Mediators/toxicity, Insulin-Secreting Cells/drug effects, Insulin-Secreting Cells/metabolism, Insulin-Secreting Cells/pathology, Lysosomes/drug effects, Lysosomes/metabolism, Male, Mechanistic Target of Rapamycin Complex 1/metabolism, Mitochondrial Degradation/drug effects, Models, Biological, Multivesicular Bodies/drug effects, Multivesicular Bodies/metabolism, Multivesicular Bodies/ultrastructure, Rats, Wistar, Signal Transduction/drug effects, Time Factors, Transcription Factor CHOP/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
01/02/2018 21:55
Last modification date
20/08/2019 16:48
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