Inhibition of PRMT5 attenuates cerebral ischemia/reperfusion–Induced inflammation and pyroptosis through suppression of NF–κB/NLRP3 axis

• Published in: Neuroscience letters 2022-04, Vol.776, p.136576-136576, Article 136576
• Main Authors: Wu, Xiang, Wang, Bo, Li, Jiaxi, Yang, Zhongbo, Zhou, Yunfei, Ma, Xudong, Kou, Zhiyan, Jiang, Liangchao, Song, Jinning
• Format: Article
• Language: English
• Subjects: Animals; Brain Ischemia - metabolism; Cerebral I/R; Inflammasomes - metabolism; Inflammation; Mice; NF-kappa B - metabolism; NF-κB; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3; PRMT5; Protein-Arginine N-Methyltransferases; Pyroptosis; Reperfusion; Reperfusion Injury - metabolism
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2022.136576

•we have reported for the first time that PRMT5 expression was up-regulated in both cell and animal I/R models.•Inhibition of PRMT5 attenuates cerebral I/R–induced infammation and pyroptosis.•Rescue experiment proved that the pro-infammatory and pro-pyroptotic effect of PRMT5 was the consequence of activation of NF-κB/NLRP3 axis. Protein methylation is a prevalent post-translational modification after cerebral ischemia. Protein arginine methyltransferase 5 (PRMT5) is a type of methyltransferase enzyme that can catalyse the formation of methylated residues on histones and non-histone proteins. Accumulating evidence suggested that PRMT5 might play a carcinogenic role in various cancers. However, the role of PRMT5 in cerebral ischaemia/reperfusion (I/R) injury remains unclear. In this project, middle cerebral artery occlusion/reperfusion (MCAO/R) model in mice and oxygen-glucose deprivation/reoxygenation (OGD/R) model in human neuroblastoma SH-SY5Y cells were utilized to mimic disease state of cerebral I/R. We found that expression of inflammatory-related factors [Interleukin (IL)-1β and IL-6)] and pyroptotic-related factor [N-term cleaved Gasdermin-D (GSDMD-N)] were up-regulated in both MCAO/R mice and OGD/R SH-SY5Y cells. In addition, both in vivo and in vitro, PRMT5 was aberrantly upregulated during cerebral I/R. However, these alterations induced by I/R were blocked by PRMT5 inhibitor LLY-283, and enhanced by overexpression of PRMT5. Furthermore, rescue experiment proved that PRMT5 plays a pro-inflammatory and pro-pyroptotic role by activating nuclear factor kappa B (NF-κB)/nucleotide-binding oligomerization domainlike receptor pyrin domain containing 3 (NLRP3) axis. Finally, we observed that treatment of LLY-283 alleviated neurological deficits and reduced infarct volume in the MCAO/R mice. Taken together, PRMT5 may be a potential therapeutic target for cerebral I/R injury.