Activation of the NLRP3 Inflammasome Complex is Not Required for Stress-Induced Death of Pancreatic Islets |
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| Authors: | Jibran A. Wali Esteban N. Gurzov Stacey Fynch Lorraine Elkerbout Thomas W. Kay Seth L. Masters Helen E. Thomas |
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| Affiliation: | 1. St Vincent’s Institute, Fitzroy, Victoria, Australia.; 2. The University of Melbourne Department of Medicine, St. Vincent’s Hospital, Fitzroy, Victoria, Australia.; 3. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.; University of California Merced, United States of America, |
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| 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 invitro. 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. |
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