Neuroinflammation is a major pathogenic mechanism in neurodegenerative diseases. Understanding the regulation of neuroinflammation is critical to therapeutic development. We report here that dynamin related protein 1 (DRP1), well-recognized for its role in mitochondrial fission, is a transcription factor that regulates neuroinflammation. Using multiple inflammatory models, we provide evidence demonstrating that DRP1, when challenged with pro-inflammatory lipopolysaccharides, translocates from the cytosol to the nucleus, then binds to the promoter region of Rela (encoding NF-κB) to activate its gene products and other downstream inflammatory cytokines. Our data also demonstrate the significant role of the proinflammatory lipocalin 2 in the brain. In combination, this study highlights a previously unidentified function of DRP1 in mediating neuroinflammation via the NF-κB-lipocalin 2 axis. Through such mechanisms of DRP1, this study also provides potential therapeutic targets for neurodegenerative diseases and other conditions linked to inflammation.
