Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis.

Ruiz, Florian Peter, Benjamin Rebeaud, Jessica Vigne, Solenne Bressoud, Valentine Roumain, Martin [UCL] Wyss, Tania Yersin, Yannick Wagner, Ingrid Kreutzfeldt, Mario Pimentel Mendes, Marisa Kowalski, Camille Boivin, Gael Roth, Leonard Schwaninger, Markus Merkler, Doron Muccioli, Giulio [UCL] Hugues, Stephanie Petrova, Tatiana V Pot, Caroline et al.[show all]

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.