NLRP3 inflammasome inhibitor MCC950 reduces cerebral ischemia/reperfusion induced neuronal ferroptosis

The role of nucleotide-binding oligomerization domainlike receptor pyrin domain containing 3 (NLRP3) inflammasome in cerebral ischemia-reperfusion (I/R) induced neuroinflammation and neuronal pyroptosis has been widely recognized. Latest studies revealed that NLRP3 inflammasome engage in not only pyroptosis but also other types of cell death. Ferroptosis has been proved to be closely associated with cerebral I/R injury. In this study, our objectives were to verify the inhibitory effect of the NLRP3-specific inhibitor MCC950 on cerebral I/R-mediated neuronal pyroptosis, and to explore the regulation and possible mechanism of MCC950 on cerebral I/R-mediated neuronal ferroptosis. Our data showed that the NLRP3-specific inhibitor, MCC950, effectively reversed the I/R-mediated NLRP3 inflammasome activation and neuronal pyroptosis. Furthermore, we found that I/R increased iron concentrations and levels of malondialdehyde (MDA), downregulated glutathione peroxidase 4 (GPX4) expression, and upregulated long chain fatty acid-CoA ligase 4 (FACL4) and prostaglandin endoperoxide synthase 2 (PTGS2) expression. Interestingly, these changes were also reversed by the MCC950. Finally, in vitro, we found that MCC950 significantly reduced ROS levels in OGD/R treated HT22 cells. In conclusion, pharma-ceutical inhibition of NLRP3 by MCC950 attenuates I/R-induced neuronal ferroptosis, possibly by reducing ROS accumulation.

Automated summary

The study confirms the inhibitory effect of the NLRP3-specific inhibitor MCC950 on neuroinflammation and neuronal pyroptosis induced by cerebral ischemia-reperfusion (I/R), and explores the regulation and mechanism of MCC950 on neuronal ferroptosis induced by cerebral I/R. The results show that MCC950 effectively reverses the activation of NLRP3 inflammasome and neuronal pyroptosis induced by I/R. The study also reveals that MCC950 can reduce iron concentrations and levels of malondialdehyde (MDA), upregulate glutathione peroxidase 4 (GPX4) expression, and downregulate long chain fatty acid-CoA ligase 4 (FACL4) and prostaglandin endoperoxide synthase 2 (PTGS2) expression induced by I/R. Furthermore, MCC950 significantly reduces ROS levels in OGD/R treated HT22 cells.