25-hydroxycholesterol promotes brain cytokine production and leukocyte infiltration in a mouse model of lipopolysaccharide-induced neuroinflammation.
Animals
Lipopolysaccharides
/ toxicity
Hydroxycholesterols
/ metabolism
Mice
Cytokines
/ metabolism
Male
Brain
/ metabolism
Female
Leukocytes
/ drug effects
Mice, Inbred C57BL
Disease Models, Animal
Mice, Knockout
Neuroinflammatory Diseases
/ metabolism
Steroid Hydroxylases
/ metabolism
Microglia
/ metabolism
Cells, Cultured
25-hydroxycholesterol
Alzheimer’s disease
Cholesterol-25-hydroxylase
Cytokines
Lipopolysaccharide
Microglial activation
Neuroinflammation
Neutrophil infiltration
Toll-like receptor-4
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
05 Oct 2024
05 Oct 2024
Historique:
received:
22
07
2024
accepted:
12
09
2024
medline:
6
10
2024
pubmed:
6
10
2024
entrez:
5
10
2024
Statut:
epublish
Résumé
Neuroinflammation has been implicated in the pathogenesis of several neurologic and psychiatric disorders. Microglia are key drivers of neuroinflammation and, in response to different inflammatory stimuli, overexpress a proinflammatory signature of genes. Among these, Ch25h is a gene overexpressed in brain tissue from Alzheimer's disease as well as various mouse models of neuroinflammation. Ch25h encodes cholesterol 25-hydroxylase, an enzyme upregulated in activated microglia under conditions of neuroinflammation, that hydroxylates cholesterol to form 25-hydroxycholesterol (25HC). 25HC can be further metabolized to 7α,25-dihydroxycholesterol, which is a potent chemoattractant of leukocytes. We have previously shown that 25HC increases the production and secretion of the proinflammatory cytokine, IL-1β, by primary mouse microglia treated with lipopolysaccharide (LPS). In the present study, wildtype (WT) and Ch25h-knockout (KO) mice were peripherally administered LPS to induce an inflammatory state in the brain. In LPS-treated WT mice, Ch25h expression and 25HC levels increased in the brain relative to vehicle-treated WT mice. Among LPS-treated WT mice, females produced significantly higher levels of 25HC and showed transcriptomic changes reflecting higher levels of cytokine production and leukocyte migration than WT male mice. However, females were similar to males among LPS-treated KO mice. Ch25h-deficiency coincided with decreased microglial activation in response to systemic LPS. Proinflammatory cytokine production and intra-parenchymal infiltration of leukocytes were significantly lower in KO compared to WT mice. Amounts of IL-1β and IL-6 in the brain strongly correlated with 25HC levels. Our results suggest a proinflammatory role for 25HC in the brain following peripheral administration of LPS.
Identifiants
pubmed: 39369253
doi: 10.1186/s12974-024-03233-1
pii: 10.1186/s12974-024-03233-1
doi:
Substances chimiques
Lipopolysaccharides
0
Hydroxycholesterols
0
Cytokines
0
25-hydroxycholesterol
767JTD2N31
cholesterol 25-hydroxylase
EC 1.14.99.38
Steroid Hydroxylases
EC 1.14.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
251Subventions
Organisme : NIH HHS
ID : R01AG081419
Pays : United States
Informations de copyright
© 2024. The Author(s).
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