Phoenixin-20 Ameliorates Lipopolysaccharide-Induced Activation of Microglial NLRP3 Inflammasome.

Abstract

Injury associated with neuroinflammation has been linked with several kinds of neurodegenerative diseases. The activation of the NLRP3 inflammasome plays an important role in microglia-mediated inflammation. Phoenixin (PNX)-20 is a newly discovered neuropeptide with pleiotropic effects involved in the regulation of reproductive and cognitive function, depression, and food uptake. This study investigated whether PNX-20 possesses a protective effect against lipopolysaccharide (LPS)-induced activation of the NLRP3 inflammasome in microglia. Firstly, our results show that the PNX-20 treatment significantly prevented LPS-induced expression of NADPH oxidase 4 (NOX-4) and the generation of reactive oxygen species (ROS). Secondly, PNX-20 mitigated LPS-induced upregulation of TxNIP, an upstream regulator of NLRP3 inflammasome activation. Thirdly, further evaluation of the major components of the NLRP3 inflammasome revealed that PNX-20 inhibited LPS-mediated upregulation of NLRP3, ASC, and cleaved caspase-1 (P10). Notably, based on our results, the inhibitory effect of PNX-20 on the NLRP3 inflammasome results in the inhibition of IL-1β and IL-18 secretions. Finally, we found that PNX-20 ameliorated the reduction in SIRT1 expression induced by LPS. When microglial SIRT1 was inhibited by nicotine, PNX-20 lost its suppressive effect on the expression of NLRP3, ASC, and caspase-1, as well as the secretion of IL-1β and IL-18. As a result of these findings, we draw the conclusion that the neuroprotective effect of PNX-20 is dependent on SIRT1. Collectively, the study shows that PNX-20 has a regulatory effect via modulation of neuroinflammation.