title: Activation of the NLRP3 inflammasome complex is not required for stress-induced death of pancreatic islets.
abstract: Loss of pancreatic beta cells is a feature of type-2 diabetes. High glucose concentrations induce endoplasmic reticulum (ER) and oxidative stress-mediated apoptosis of islet cells in vitro. ER stress, oxidative stress and high glucose concentrations may also activate the NLRP3 inflammasome leading to interleukin (IL)-1β production and caspase-1 dependent pyroptosis. However, whether IL-1β or intrinsic NLRP3 inflammasome activation contributes to beta cell death is controversial. This possibility was examined in mouse islets. Exposure of islets lacking functional NLRP3 or caspase-1 to H2O2, rotenone or thapsigargin induced similar cell death as in wild-type islets. This suggests that oxidative or ER stress do not cause inflammasome-mediated cell death. Similarly, deficiency of NLRP3 inflammasome components did not provide any protection from glucose, ribose or gluco-lipotoxicity. Finally, genetic activation of NLRP3 specifically in beta cells did not increase IL-1β production or cell death, even in response to glucolipotoxicity. Overall, our results show that glucose-, ER stress- or oxidative stress-induced cell death in islet cells is not dependent on intrinsic activation of the NLRP3 inflammasome.
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria, Australia; The University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Jibran A
authors.initials: JA
authors.lastname: Wali
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria, Australia; The University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria, Australia.
authors.forename: Stacey
authors.initials: S
authors.lastname: Fynch
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria, Australia.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Elkerbout
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria, Australia; The University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Kay
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: St Vincent's Institute, Fitzroy, Victoria, Australia; The University of Melbourne Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D007515:Islets of Langerhans / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016133:Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse