Activation of the NLRP3 inflammasome complex is not required for stress-induced death of pancreatic islets

• Published in: PloS one 2014-11, Vol.9 (11), p.e113128-e113128
• Main Authors: Wali, Jibran A, Gurzov, Esteban N, Fynch, Stacey, Elkerbout, Lorraine, Kay, Thomas W, Masters, Seth L, Thomas, Helen E
• Format: Article
• Language: English
• Subjects: Activation; Analysis of Variance; Animals; Apoptosis; Apoptosis - physiology; Beta cells; Biology and Life Sciences; Blotting, Western; Carrier Proteins - metabolism; Caspase; Caspase-1; Cell activation; Cell death; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - metabolism; DNA Primers - genetics; Endoplasmic reticulum; Endoplasmic Reticulum Stress - physiology; Enzyme-Linked Immunosorbent Assay; Gene expression; Genotype; Glucose; Hospitals; Hydrogen peroxide; IL-1β; Inflammasomes; Insulin; Interleukin; Interleukins; Islet cells; Islets of Langerhans; Islets of Langerhans - metabolism; Islets of Langerhans - physiopathology; Kinases; Laboratories; Medicine; Medicine and Health Sciences; Mice; Mortality; NLR Family, Pyrin Domain-Containing 3 Protein; Oxidative stress; Pancreas; Pancreatic beta cells; Polymerase Chain Reaction; Proteins; Pyroptosis; Ribose; Rodents; Rotenone; Thapsigargin; Toxicity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0113128

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.