25-Hydroxycholesterol suppress IFN-γ-induced inflammation in microglia by disrupting lipid raft formation and caveolin-mediated signaling endosomes
Jee Hoon Lee, Ji‐Hye Han, Joo Hong Woo, Ilo Jou
Abstract
Acute microglial activation plays an important role in neuroprotection. However, dysregulated, prolonged microgliosis exacerbates neurodegeneration through excessive release of pro-inflammatory cytokines and cytotoxic factors. Interferon-gamma (IFN-γ), an inflammatory cytokine, exacerbates the detrimental microglial response. Although various anti-inflammatory drugs have been evaluated as interventions for microglia-mediated neuroinflammation, no anti-inflammatories are in clinical use for microgliosis. The present study evaluated the anti-inflammatory mechanisms of oxysterols, blood brain barrier (BBB) penetrable bioactive lipids, revealing that this intervention suppresses neuroinflammation by disrupting membrane lipid raft formation and caveolae-mediated endosomal IFN-γ signaling. We find that 25-hydroxycholesterol (25-HC) rapidly repressed IFN-γ receptor trafficking to lipid rafts in microglia by disrupting raft formation, thereby suppressing microglial inflammatory response. IFN-γ treatment upregulated expression of Cav-1, a major component of caveolae, and IFN-γ signaling was sustained through Cav-1+ signaling endosomes. 25-HC repressed IFN-γ induction of Cav-1 expression in microglia, and subsequently suppressed the chronic inflammatory response. Taken together, these findings demonstrated that 25-HC effectively regulate the inflammatory status of microglia by mediating the formation of rafts and caveolae-dependent signaling endosomes. Given the important roles of IFN-γ and microglia in the pathology of neurodegenerative brain diseases, a novel anti-inflammatory mechanism of 25-HC that is not receptor-dependent, but rather is related to the regulation of membrane rafts and caveolae, suggests a new therapeutic target for inflammatory neurodegenerations.