Long non-coding RNA NEAT1 modulates microglial NLRP3 inflammasome activation

Abstract

Microglia, the resident macrophages in the central nervous system (CNS), play a fundamental role in maintaining CNS homeostasis and responding to immune challenges. Dysregulated microglial activation and subsequent neuroinflammation are associated with various CNS diseases. A key mechanism driving neuroinflammation is the activation of the NLRP3 inflammasome complex triggered by diverse molecular motifs. The microglial NLRP3 inflammasome activation has been implicated in a plethora of diseases, including cardiovascular, autoimmune, and neurodegenerative diseases. Long non-coding RNAs (lncRNAs), particularly Nuclear Enriched Abundant Transcript 1 (NEAT1), have emerged as essential players in gene regulation and inflammation. In this study, we investigated the role of NEAT1 in microglial NLRP3 inflammasome activation utilizing in vitro and in vivo models. Our in vivo studies showed that NEAT1 knockout alleviates NLRP3 inflammasome activation in LPS-injected NEAT1 KO mice. Additionally, our in vitro studies confirmed these findings, demonstrating that NEAT1 expression is upregulated upon NLRP3 inflammasome activation in microglia. Further experiments revealed that NEAT1 depletion with siRNA significantly attenuated NLRP3 inflammasome activation and the release of pro-inflammatory cytokine IL-1β. Mechanistically, we found that NEAT1 interacted with RNA-binding proteins to regulate NLRP3 inflammasome activation. Given the central role of microglial NLRP3 inflammasome activation in neuroinflammation, our findings elaborated the regulatory mechanisms involving NEAT1, thus offering potential therapeutic avenues for CNS disorders.