| First Author | Sokolova M | Year | 2018 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 315 |
| Issue | 5 | Pages | E912-E923 |
| PubMed ID | 30016155 | Mgi Jnum | J:274029 |
| Mgi Id | MGI:6283228 | Doi | 10.1152/ajpendo.00461.2017 |
| Citation | Sokolova M, et al. (2018) NLRP3 inflammasome mediates oxidative stress-induced pancreatic islet dysfunction. Am J Physiol Endocrinol Metab 315(5):E912-E923 |
| abstractText | 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. |
