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

• Published in: Free radical biology & medicine 2022-02, Vol.179, p.252-265
• Main Authors: Lee, Jee Hoon, Han, Ji-hye, Woo, Joo Hong, Jou, Ilo
• Format: Article
• Language: English
• Subjects: 25-Hydroxycholesterol; Animals; Caveolin-1; Caveolins; Endosomes; Hydroxycholesterols - pharmacology; IFN-γ; Inflammation; Interferon-gamma - genetics; Lipid raft; Membrane Microdomains; Mice; Mice, Inbred C57BL; Microglia; Neurodegenerative diseases; Neuroinflammatory Diseases; Oxysterols; Signaling endosome
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2021.11.017

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. [Display omitted] •25-HC suppress IFN-γ inflammatory signaling in microglia by disrupting lipid raft formation.•Caveolin-1-mediated signaling endosome cause prolonged IFN-γ signaling.•25-HC suppress Caveolin-1-mediated IFN-γ signaling endosome formation.•25-HC ameliorate microglial inflammation in the LRRK2-G2019S PD model.