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25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner.

Publication ,  Journal Article
Wong, MY; Lewis, M; Doherty, JJ; Shi, Y; Cashikar, AG; Amelianchik, A; Tymchuk, S; Sullivan, PM; Qian, M; Covey, DF; Petsko, GA; Holtzman, DM ...
Published in: J Neuroinflammation
June 17, 2020

BACKGROUND: Genome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular and chemical mediators of neuroinflammation in AD remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling and innate immunity. Cholesterol 25-hydroxylase (CH25H), the enzyme responsible for 25-HC production, has also been found to be one of the disease-associated microglial (DAM) genes that are upregulated in the brain of AD and AD transgenic mouse models. METHODS: We used real-time PCR and immunoblotting to examine CH25H expression in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. The innate immune response of primary mouse microglia under different treatment conditions or bearing different genetic backgrounds was analyzed using ELISA, western blotting, or immunocytochemistry. RESULTS: We found that CH25H expression is upregulated in human AD brain tissue and in transgenic mouse brain tissue-bearing amyloid-β plaques or tau pathology. Treatment with the toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates CH25H expression in the mouse brain and stimulates CH25H expression and 25-HC secretion in mouse primary microglia. We found that LPS-induced microglial production of the pro-inflammatory cytokine IL-1β is markedly potentiated by 25-HC and attenuated by the deletion of CH25H. Microglia expressing apolipoprotein E4 (apoE4), a genetic risk factor for AD, produce greater amounts of 25-HC than apoE3-expressing microglia following treatment with LPS. Remarkably, 25-HC treatment results in a greater level of IL-1β secretion in LPS-activated apoE4-expressing microglia than in apoE2- or apoE3-expressing microglia. Blocking potassium efflux or inhibiting caspase-1 prevents 25-HC-potentiated IL-1β release in apoE4-expressing microglia, indicating the involvement of caspase-1 inflammasome activity. CONCLUSION: 25-HC may function as a microglial-secreted inflammatory mediator in the brain, promoting IL-1β-mediated neuroinflammation in an apoE isoform-dependent manner (E4>>E2/E3) and thus may be an important mediator of neuroinflammation in AD.

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Published In

J Neuroinflammation

DOI

EISSN

1742-2094

Publication Date

June 17, 2020

Volume

17

Issue

1

Start / End Page

192

Location

England

Related Subject Headings

  • tau Proteins
  • Steroid Hydroxylases
  • Neurology & Neurosurgery
  • Microglia
  • Mice, Transgenic
  • Mice
  • Lipopolysaccharides
  • Interleukin-1beta
  • Hydroxycholesterols
  • Humans
 

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Wong, M. Y., Lewis, M., Doherty, J. J., Shi, Y., Cashikar, A. G., Amelianchik, A., … Luo, W. (2020). 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner. J Neuroinflammation, 17(1), 192. https://doi.org/10.1186/s12974-020-01869-3
Wong, Man Ying, Michael Lewis, James J. Doherty, Yang Shi, Anil G. Cashikar, Anna Amelianchik, Svitlana Tymchuk, et al. “25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner.J Neuroinflammation 17, no. 1 (June 17, 2020): 192. https://doi.org/10.1186/s12974-020-01869-3.
Wong MY, Lewis M, Doherty JJ, Shi Y, Cashikar AG, Amelianchik A, et al. 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner. J Neuroinflammation. 2020 Jun 17;17(1):192.
Wong, Man Ying, et al. “25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner.J Neuroinflammation, vol. 17, no. 1, June 2020, p. 192. Pubmed, doi:10.1186/s12974-020-01869-3.
Wong MY, Lewis M, Doherty JJ, Shi Y, Cashikar AG, Amelianchik A, Tymchuk S, Sullivan PM, Qian M, Covey DF, Petsko GA, Holtzman DM, Paul SM, Luo W. 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner. J Neuroinflammation. 2020 Jun 17;17(1):192.
Journal cover image

Published In

J Neuroinflammation

DOI

EISSN

1742-2094

Publication Date

June 17, 2020

Volume

17

Issue

1

Start / End Page

192

Location

England

Related Subject Headings

  • tau Proteins
  • Steroid Hydroxylases
  • Neurology & Neurosurgery
  • Microglia
  • Mice, Transgenic
  • Mice
  • Lipopolysaccharides
  • Interleukin-1beta
  • Hydroxycholesterols
  • Humans