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25-Hydroxycholesterol suppress IFN-γ-induced inflammation in microglia by disrupting lipid raft formation and caveolin-mediated signaling endosomes

Lee, JH | Han, JH | Woo, JH  | Jou, I
Free radical biology & medicine, 179. : 252-265, 2022
Journal Title
Free radical biology & medicine
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-gamma), 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-gamma signaling. We find that 25-hydroxycholesterol (25-HC) rapidly repressed IFN-gamma receptor trafficking to lipid rafts in microglia by disrupting raft formation, thereby suppressing microglial inflammatory response. IFN-gamma treatment upregulated expression of Cav-1, a major component of caveolae, and IFN-gamma signaling was sustained through Cav-1(+) signaling endosomes. 25-HC repressed IFN-gamma 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-gamma 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.


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Journal Papers > Research Organization > Inflamm-aging Translational Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
Ajou Authors
우, 주홍  |  주, 일로
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