25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner.
Alzheimer Disease
/ genetics
Amyloid beta-Peptides
/ metabolism
Animals
Apolipoproteins E
/ genetics
Frontal Lobe
/ drug effects
Humans
Hydroxycholesterols
/ metabolism
Interleukin-1beta
/ metabolism
Lipopolysaccharides
/ pharmacology
Mice
Mice, Transgenic
Microglia
/ drug effects
Steroid Hydroxylases
/ genetics
tau Proteins
/ metabolism
25-Hydroxycholesterol
Alzheimer’s disease
Apolipoprotein E
Cholesterol 25-hydroxylase
Inflammasome
Inflammation
Interleukin-1β
Lipid metabolism
Lipopolysaccharide
Microglia
Oxysterol
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
17 Jun 2020
17 Jun 2020
Historique:
received:
26
02
2020
accepted:
08
06
2020
entrez:
20
6
2020
pubmed:
20
6
2020
medline:
21
5
2021
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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
CONCLUSIONS
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.
Identifiants
pubmed: 32552741
doi: 10.1186/s12974-020-01869-3
pii: 10.1186/s12974-020-01869-3
pmc: PMC7298825
doi:
Substances chimiques
Amyloid beta-Peptides
0
Apolipoproteins E
0
Hydroxycholesterols
0
Interleukin-1beta
0
Lipopolysaccharides
0
tau Proteins
0
25-hydroxycholesterol
767JTD2N31
Steroid Hydroxylases
EC 1.14.-
cholesterol 25-hydroxylase
EC 1.14.99.38
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
192Subventions
Organisme : Washington University-Centene Personalize Medicine Initiative
ID : NA
Organisme : NIH HHS
ID : MH110550
Pays : United States
Organisme : JPB Foundation
ID : NA
Organisme : NIA NIH HHS
ID : AG047644
Pays : United States
Organisme : NIA NIH HHS
ID : NS090934
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH110550
Pays : United States
Organisme : Appel Alzheimer's disease Research institute
ID : NA
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