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.
| Original language | English |
|---|---|
| Article number | e55328 |
| Journal | EMBO Reports |
| Volume | 24 |
| Issue number | 3 |
| Pages (from-to) | e55328 |
| ISSN | 1469-221X |
| DOIs | |
| Publication status | Published - 06.2023 |
Funding
We would like to thank R. Adams, M. Fruttiger, and T. Makinen for providing Cdh5-CreERT2, Pdgfb-iCreERT2 mice and Prox1-CreERT2 mouse strains, the Lausanne Genomic Technologies Facility for performing the RNA sequencing, the Lausanne University Metabolomic Unit for performing eicosanoids measurement, the Flow Cytometry Facility of the Lausanne University for performing cell sorting experiments and the Mouse Pathology Facility for histology experiments. The synopsis graphical abstract was created with Biorender (agreement number: EW24MC26H6). This work was supported by the Leenaards Foundation (to CP, SH and TVP), the Swiss National Science Foundation (PP00P3-157476 to CP; 310030-192738 to CP; MD-PhD grant 323630-183987 to FR) and the Biaggi Foundation (to CP). Open access funding provided by Universite de Lausanne. We would like to thank R. Adams, M. Fruttiger, and T. Makinen for providing Cdh5‐CreERT2, Pdgfb‐iCreERT2 mice and Prox1‐CreERT2 mouse strains, the Lausanne Genomic Technologies Facility for performing the RNA sequencing, the Lausanne University Metabolomic Unit for performing eicosanoids measurement, the Flow Cytometry Facility of the Lausanne University for performing cell sorting experiments and the Mouse Pathology Facility for histology experiments. The synopsis graphical abstract was created with Biorender (agreement number: EW24MC26H6). This work was supported by the Leenaards Foundation (to CP, SH and TVP), the Swiss National Science Foundation (PP00P3‐157476 to CP; 310030‐192738 to CP; MD‐PhD grant 323630‐183987 to FR) and the Biaggi Foundation (to CP). Open access funding provided by Universite de Lausanne.
