NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date


Document Type



Cellular and Molecular Physiology | Endocrinology | Immunology and Infectious Disease


Inflammasomes are multiprotein inflammatory platforms that induce caspase-1 activation and subsequently interleukin (IL)-1beta and IL-18 processing. The NLRP3 inflammasome is activated by different forms of oxidative stress, and, based on the central role of IL-1beta 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 beta-cell death and reduced macrophage infiltration. This suggests that the beneficial effect of NLRP3 inflammasome deficiency on oxidative stress-mediated beta-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 beta-cell preservation.


NLRP3 inflammasome, clodronate, macrophages, oxidative stress-induced diabetes, pancreatic islets

DOI of Published Version



Sokolova M, Sahraoui A, Høyem M, Øgaard J, Lien E, Aukrust P, Yndestad A, Ranheim T, Scholz H. NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction. Am J Physiol Endocrinol Metab. 2018 Nov 1;315(5):E912-E923. doi: 10.1152/ajpendo.00461.2017. Epub 2018 Jul 17. PMID: 30016155. Link to article on publisher's site

Journal/Book/Conference Title

American journal of physiology. Endocrinology and metabolism

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