title: Oxysterols regulate encephalitogenic CD4(+) T cell trafficking during central nervous system autoimmunity.
abstract: Perturbation of steroids pathways is linked to inflammation and chronic diseases, however the underlying mechanism remains unclear. Oxysterols, oxidized forms of cholesterol, are not only essential for bile synthesis and sterol transportation but have recently been shown to contribute to the immune response. In addition, serum oxysterols levels have been proposed as suitable candidate biomarkers for neurological diseases such as multiple sclerosis (MS). However how oxysterols modulate adaptive immunity is unknown and their functions in autoimmunity have not been investigated. The enzyme cholesterol 25 hydroxylase (Ch25h) is the rate limiting step to synthesize the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) from cholesterol. We here report, using the MS murine model experimental autoimmune encephalomyelitis (EAE), that Ch25h deletion significantly attenuated EAE disease course by limiting trafficking of pathogenic CD4(+) T lymphocytes to the central nervous system (CNS). Mechanistically, we show a critical involvement for oxysterols in recruiting leukocytes into inflamed tissues and propose that 7α,25-OHC preferentially promotes the migration of activated CD44(+)CD4(+) T cells by binding the G protein-coupled receptor called Epstein-Barr virus induced gene 2 (EBI2). Collectively, our results support a pro-inflammatory role for oxysterols during EAE and identify oxysterols as a potential therapeutic target to treat autoimmune diseases.
authors.affiliation: Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospitals, 1211 Geneva 14, Switzerland; Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Chalmin
authors.affiliation: Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospitals, 1211 Geneva 14, Switzerland; Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Rochemont
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Lippens
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Clottu
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Basel, Switzerland.
authors.forename: A W
authors.initials: AW
authors.lastname: Sailer
authors.affiliation: Department of Pathology and Immunology, Division of Clinical Pathology, University & University Hospital of Geneva, Switzerland; Department of Neuropathology, Georg-August-University Goettingen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Merkler
authors.affiliation: Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Hugues
authors.affiliation: Division of Neurology, Department of Clinical Neurosciences, Geneva University Hospitals, 1211 Geneva 14, Switzerland; Department of Pathology and Immunology, University of Geneva, 1211 Geneva 4, Switzerland. Electronic address: Caroline.Pot@unige.ch.
authors.forename: C
authors.initials: C
authors.lastname: Pot
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D015551:Autoimmunity; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006888:Hydroxycholesterols / Q000494:pharmacology*; D020381:Interleukin-17 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000172:deficiency / Q000235:genetics
chemical_list: D000941:Antigens; D016207:Cytokines; C543809:Gpr183 protein, mouse; D018960:Hyaluronan Receptors; D006888:Hydroxycholesterols; D020381:Interleukin-17; D043562:Receptors, G-Protein-Coupled; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase
keywords: Autoimmunity; CD4(+) T lymphocytes; Cholesterol 25 hydroxylase (Ch25h); Experimental autoimmune encephalomyelitis; Oxysterols; Trafficking