Side-Chain Immune Oxysterols Induce Neuroinflammation by Activating Microglia

• Published in: International journal of molecular sciences Vol. 24; no. 20; p. 15288
• Main Authors: Son, Yonghae, Yeo, In-Jun, Hong, Jin-Tae, Eo, Seong-Kug, Lee, Dongjun, Kim, Koanhoi
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.10.2023; MDPI
• Subjects: Alzheimer's disease; Apolipoproteins; Brain; Cholesterol; Cytotoxicity; Immunohistochemistry; Inflammation; Kinases; Nervous system diseases; Oxidation; Pathogenesis; Phosphorylation; Proteins; South Korea
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms242015288

In individuals with Alzheimer’s disease, the brain exhibits elevated levels of IL-1β and oxygenated cholesterol molecules (oxysterols). This study aimed to investigate the effects of side-chain oxysterols on IL-1β expression using HMC3 microglial cells and ApoE-deficient mice. Treatment of HMC3 cells with 25-hydroxycholesterol (25OHChol) and 27-hydroxycholesterol (27OHChol) led to increased IL-1β expression at the transcript and protein levels. Additionally, these oxysterols upregulated the surface expression of MHC II, a marker of activated microglia. Immunohistochemistry performed on the mice showed increased microglial expression of IL-1β and MHC II when fed a high-cholesterol diet. However, cholesterol and 24s-hydroxycholesterol did not increase IL-1β transcript levels or MHC II expression. The extent of IL-1β increase induced by 25OHChol and 27OHChol was comparable to that caused by oligomeric β-amyloid, and the IL-1β expression induced by the oxysterols was not impaired by polymyxin B, which inhibited lipopolysaccharide-induced IL-1β expression. Both oxysterols enhanced the phosphorylation of Akt, ERK, and Src, and inhibition of these kinase pathways with pharmacological inhibitors suppressed the expression of IL-1β and MHC II. The pharmacological agents chlorpromazine and cyclosporin A also impaired the oxysterol-induced expression of IL-1β and upregulation of MHC II. Overall, these findings suggest that dysregulated cholesterol metabolism leading to elevated levels of side-chain oxysterols, such as 25OHChol and 27OHChol, can activate microglia to secrete IL-1β through a mechanism amenable to pharmacologic intervention. The activation of microglia and subsequent neuroinflammation elicited by the immune oxysterols can contribute to the development of neurodegenerative diseases.