Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis.
cholesterol-25-hydroxylase
endothelial cells
experimental autoimmune encephalomyelitis
oxysterols
polymorphonuclear myeloid-derived suppressor cells
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
06 03 2023
06 03 2023
Historique:
revised:
21
12
2022
received:
29
04
2022
accepted:
05
01
2023
pubmed:
31
1
2023
medline:
8
3
2023
entrez:
30
1
2023
Statut:
ppublish
Résumé
The vasculature is a key regulator of leukocyte trafficking into the central nervous system (CNS) during inflammatory diseases including multiple sclerosis (MS). However, the impact of endothelial-derived factors on CNS immune responses remains unknown. Bioactive lipids, in particular oxysterols downstream of Cholesterol-25-hydroxylase (Ch25h), promote neuroinflammation but their functions in the CNS are not well-understood. Using floxed-reporter Ch25h knock-in mice, we trace Ch25h expression to CNS endothelial cells (ECs) and myeloid cells and demonstrate that Ch25h ablation specifically from ECs attenuates experimental autoimmune encephalomyelitis (EAE). Mechanistically, inflamed Ch25h-deficient CNS ECs display altered lipid metabolism favoring polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) expansion, which suppresses encephalitogenic T lymphocyte proliferation. Additionally, endothelial Ch25h-deficiency combined with immature neutrophil mobilization into the blood circulation nearly completely protects mice from EAE. Our findings reveal a central role for CNS endothelial Ch25h in promoting neuroinflammation by inhibiting the expansion of immunosuppressive myeloid cell populations.
Identifiants
pubmed: 36715148
doi: 10.15252/embr.202255328
pmc: PMC9986812
doi:
Substances chimiques
Oxysterols
0
Banques de données
GEO
['GSE217431']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e55328Subventions
Organisme : Swiss National Science Foundation
ID : PP00P3-157476
Pays : Switzerland
Organisme : Swiss National Science Foundation
ID : 310030-192738
Pays : Switzerland
Organisme : Swiss National Science Foundation
ID : 323630-183987
Pays : Switzerland
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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