Title

NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction

UMMS Affiliation

Department of Medicine, Division of Infectious Diseases and Immunology

Publication Date

2018-11-01

Document Type

Article

Disciplines

Cellular and Molecular Physiology | Endocrinology | Immunology and Infectious Disease

Abstract

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.

Keywords

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

DOI of Published Version

10.1152/ajpendo.00461.2017

Source

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

Related Resources

Link to Article in PubMed

PubMed ID

30016155

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