NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction.

Abstract

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.

• Authors: Marina Sokolova, Afaf Sahraoui, Merete Høyem, Jonas Øgaard, Egil Lien, Pål Aukrust, Arne Yndestad, Trine Ranheim, Hanne Scholz
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 315 Issue 5 Pg. E912-E923 (11 01 2018) ISSN: 1522-1555 [Electronic] United States
• PMID: 30016155 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein

Topics

• 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, metabolism)
• Oxidative Stress (physiology)