NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction

Inflammasomes are multiprotein inflammatory platforms that induce caspase-1 activation and subsequently interleukin (IL)-1β and IL-18 processing. The NLRP3 inflammasome is activated by different forms of oxidative stress, and, based on the central role of IL-1β in the destruction of pancreatic islet...

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Published in:American journal of physiology: endocrinology and metabolism 2018-11, Vol.315 (5), p.E912-E923
Main Authors: Sokolova, Marina, Sahraoui, Afaf, Høyem, Merete, Øgaard, Jonas, Lien, Egil, Aukrust, Pål, Yndestad, Arne, Ranheim, Trine, Scholz, Hanne
Format: Article
Language:English
Subjects:
Animals
Apoptosis - physiology
Diabetes Mellitus, Experimental - metabolism
Inflammasomes - metabolism
Insulin-Secreting Cells - metabolism
Interleukin-1beta - metabolism
Islets of Langerhans - metabolism
Macrophage Activation - physiology
Mice
Mice, Knockout
NLR Family, Pyrin Domain-Containing 3 Protein - genetics
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
Oxidative Stress - physiology
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Summary:Inflammasomes are multiprotein inflammatory platforms that induce caspase-1 activation and subsequently interleukin (IL)-1β and IL-18 processing. The NLRP3 inflammasome is activated by different forms of oxidative stress, and, based on the central role of IL-1β in the destruction of pancreatic islets, it could be related to the development of diabetes. We therefore investigated responses in wild-type C57Bl/6 (WT) mice, NLRP3 mice, and mice deficient in apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) after exposing islets to short-term hypoxia or alloxan-induced islet damage. NLRP3-deficient islets compared with WT islets had preserved function ex vivo and were protected against hypoxia-induced cell death. Furthermore, NLRP3 and ASC-deficient mice were protected against oxidative stress-induced diabetes caused by repetitive low-dose alloxan administration, and this was associated with reduced β-cell death and reduced macrophage infiltration. This suggests that the beneficial effect of NLRP3 inflammasome deficiency on oxidative stress-mediated β-cell damage could involve reduced macrophage infiltration and activation. To support the role of macrophage activation in alloxan-induced diabetes, we injected WT mice with liposomal clodronate, which causes macrophage depletion before induction of a diabetic phenotype by alloxan treatment, resulting in improved glucose homeostasis in WT mice. We show here that the NLRP3 inflammasome acts as a mediator of hypoxia and oxidative stress in insulin-producing cells, suggesting that inhibition of the NLRP3 inflammasome could have beneficial effects on β-cell preservation.
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.00461.2017