Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis

Article Article scientifique Article Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis eng 2023-01-30 2023-03-06 author Ruiz Florian 0000-0003-1023-9720 Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Peter Benjamin Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Rebeaud Jessica Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Vigne Solenne Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Bressoud Valentine Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Roumain Martin Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium. author Wyss Tania Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research, Lausanne, Switzerland.,SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland. author Yersin Yannick Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Wagner Ingrid 0000-0003-4437-9799 Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Division of Clinical Pathology, Diagnostic Department, University Hospitals of Geneva, Geneva, Switzerland. 604950 Département de pathologie et immunologie (PATIM) author Kreutzfeldt Mario 0000-0003-0335-2733 Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Division of Clinical Pathology, Diagnostic Department, University Hospitals of Geneva, Geneva, Switzerland. 736806 Département de pathologie et immunologie (PATIM) author Pimentel Mendes Marisa Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Kowalski Camille Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland. 868748 author Boivin Gael Radio-Oncology Laboratory, Department of Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. author Roth Leonard 0000-0002-5607-7010 Department of Epidemiology and Health Systems, Centre for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne, Switzerland. author Schwaninger Markus Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, Luebeck, Germany. author Merkler Doron Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Division of Clinical Pathology, Diagnostic Department, University Hospitals of Geneva, Geneva, Switzerland. 735735 Département de pathologie et immunologie (PATIM) author Muccioli Giulio G 0000-0002-1600-9259 Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, Brussels, Belgium. author Hugues Stéphanie Department of Pathology and Immunology, Geneva Medical School, Geneva, Switzerland. 663452 Département de pathologie et immunologie (PATIM) author Petrova Tatiana V 0000-0002-0563-6521 Department of Oncology, University of Lausanne and Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Pot Caroline 0000-0002-1146-3129 Laboratories of Neuroimmunology, Service of Neurology and Neuroscience Research Center, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland. e55328 10.15252/embr.202255328 36715148 1469-221X PMC9986812 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. Cholesterol-25-hydroxylase Endothelial cells Experimental autoimmune encephalomyelitis Oxysterols Polymorphonuclear myeloid-derived suppressor cells Mice Animals Encephalomyelitis, Autoimmune, Experimental Endothelial Cells / metabolism Oxysterols / metabolism Neuroinflammatory Diseases Central Nervous System / metabolism Mice, Inbred C57BL Dewey 616.07 137 Département de pathologie et immunologie 21F false 563 Pathologie et immunologie 906 565 La Sclérose en plaques 908 EMBO reports 24 3 ca865956-0f06-4abe-8ebf-dfd24eafc16e Article (Published version) Public Article-scientifique-from-europePmc.pdf 1844911 application/pdf CC BY-4.0 1ca7da1bec20e581c5f1d27730281929cb0bd82a5acc98738fdc16cae4c8c0e6 762ce526-9290-4aa8-aaa1-289cde17ef7e Appendix Public EMBR-24-e55328-s001.xlsx 960876 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 6867f43a9ac3266d9d652e25c74ec3bc105ebd2ba04b2e828011be12dff4c301 1076a4ae-f6ec-4767-af76-298287031d92 Appendix Public EMBR-24-e55328-s002.xlsx 11116 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 237b3ad7b719d16773565461ed6a166fed7f708a612d7b64ba86d8c8bb95d29d 8f406b71-25ba-404a-94f6-fc0fb99d8633 Appendix Public EMBR-24-e55328-s003.pdf 6110034 application/pdf a4109569103f282bf428960b6cbc9cad78ef087a4159eac03d0462fdc848b0fb 1d5d9f0d-0b9c-485d-a91f-32ea08da9539 Appendix Public EMBR-24-e55328-s004.xlsx 944447 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 43afafc2fe2d3b77426bac58f370bb206133d05d368ca54e36f71392d389e04a 6cbaf054-be16-4c37-ab1d-4cff81841e26 Appendix Public EMBR-24-e55328-s005.pdf 1852539 application/pdf 540c73e8814d43b8ea15c450b82a38dc09d332a58b01241529a917e88f451dbb ede8297e-f327-4b8c-9e99-dc08a97a2293 Appendix Public EMBR-24-e55328-s006.xlsx 931614 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet 404b488ee1501e8e87fa5a89a56e503d05ac436f0143511b83f5cc21683f50bb afdc0220-3cb6-4af3-b947-a1e5c5b6d701 Appendix Public EMBR-24-e55328-s007.pdf 388999 application/pdf 4e8258b34cff0a3280dbdac8cb38ee63f04e497827fbcb3ed8f18e2daa161b7f e44ac9a1-03c1-45fb-a2dd-a8d82bf63dc7 Appendix Public EMBR-24-e55328-s008.xlsx 930551 application/vnd.openxmlformats-officedocument.spreadsheetml.sheet f52cb9ece012abec92ddff89a188a5c47df3c7e2c66bc63c1ab69538c0b02423 openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

Title	Published in	Year	Views	Downloads

Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis	EMBO reports	2023	304	526
Macroautophagy in lymphatic endothelial cells inhibits T cell-mediated autoimmunity	Journal of Experimental Medicine	2021	394	240

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