Inhibition of GSK-3β alleviates cerebral ischemia/reperfusion injury in rats by suppressing NLRP3 inflammasome activation through autophagy.

Abstract

The nod-like receptor protein 3 (NLRP3) inflammasome has a critical role in cerebral ischemic injury, and autophagy is related to activation of the inflammasome under oxidative stress conditions. However, it is unclear how NLRP3 inflammasome activation is regulated. Glycogen synthase kinase 3β (GSK-3β) emerged as an important risk factor for brain ischemia reperfusion injury, and GSK-3β inhibits autophagic activity in many diseases. In this study, we examined whether NLRP3 inflammasome-derived inflammation could be ameliorated by GSK-3β inhibition in a cerebral ischemia reperfusion injury model and assessed whether autophagy is involved in this process. To establish ischemic reperfusion injury, we used a middle cerebral artery occlusion-reperfusion (MCAO/R) model in rats. A chemical inhibitor (SB216763) and GSK-3β siRNA were used to suppress GSK-3β activation and GSK-3β expression in vivo. The results demonstrated that SB216763 and GSK-3β siRNA improved neurological scores, reduced cerebral infarct volume, and decreased the levels of NLRP3 inflammasome, cleaved-caspase-1, IL-1β, and IL-18. Inhibiting GSK-3β activation enhanced autophagic activity (ratio of LC3B-II/LC3B-I and p62/SQSTM1), whereas treating with an autophagy inhibitor (3-MA) abrogated the inhibitory effect on NLRP3 inflammasome activation after GSK-3β inhibition. These results suggest that inhibiting GSK-3β downregulates NLRP3 inflammasome expression by increasing autophagic activity in cerebral ischemia reperfusion injury. GSK-3β might be an attractive specific target and that it functions by regulating the NLRP3 inflammasome.

• Authors: Yueting Wang, Changchang Meng, Jinyan Zhang, Jingxian Wu, Jing Zhao
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 68 Pg. 234-241 (Mar 2019) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 30703695 (Publication Type: Journal Article)
• Copyright: Copyright © 2018. Published by Elsevier B.V.

Chemical References

• IL1B protein, rat
• Indoles
• Inflammasomes
• Interleukin-18
• Interleukin-1beta
• Maleimides
• NLR Family, Pyrin Domain-Containing 3 Protein
• RNA, Small Interfering
• SB 216763
• Glycogen Synthase Kinase 3 beta

Topics

• Animals
• Autophagy (drug effects)
• Cerebral Cortex (immunology, pathology)
• Glycogen Synthase Kinase 3 beta (antagonists & inhibitors, genetics, immunology)
• Indoles (pharmacology)
• Infarction, Middle Cerebral Artery (drug therapy, immunology, pathology)
• Inflammasomes (immunology)
• Interleukin-18 (immunology)
• Interleukin-1beta (immunology)
• Male
• Maleimides (pharmacology)
• NLR Family, Pyrin Domain-Containing 3 Protein (immunology)
• RNA, Small Interfering (administration & dosage)
• Rats, Sprague-Dawley
• Reperfusion Injury (drug therapy, immunology, pathology)