Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis.
(2023) EMBO reports — Vol. 24, n° 3, p. e55328 [1-20] (2023)
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- Authors
Ruiz, Florian 
Pot, Caroline
- Abstract
- 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.
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Ruiz, F., Peter, B., Rebeaud, J., Vigne, S., Bressoud, V., Roumain, M., Wyss, T., Yersin, Y., Wagner, I., Kreutzfeldt, M., Pimentel Mendes, M., Kowalski, C., Boivin, G., Roth, L., Schwaninger, M., Merkler, D., Muccioli, G., Hugues, S., Petrova, T. V., & Pot, C. (2023). Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis. EMBO reports, 24(3), e55328 [1-20]. https://doi.org/10.15252/embr.202255328 (Original work published 2023)