title: HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation.
abstract: Lipid mediators influence immunity in myriad ways. For example, circulating sphingosine-1-phosphate (S1P) is a key regulator of lymphocyte egress. Although the majority of plasma S1P is bound to apolipoprotein M (ApoM) in the high-density lipoprotein (HDL) particle, the immunological functions of the ApoM-S1P complex are unknown. Here we show that ApoM-S1P is dispensable for lymphocyte trafficking yet restrains lymphopoiesis by activating the S1P1 receptor on bone marrow lymphocyte progenitors. Mice that lacked ApoM (Apom(-/-)) had increased proliferation of Lin(-) Sca-1(+) cKit(+) haematopoietic progenitor cells (LSKs) and common lymphoid progenitors (CLPs) in bone marrow. Pharmacological activation or genetic overexpression of S1P1 suppressed LSK and CLP cell proliferation in vivo. ApoM was stably associated with bone marrow CLPs, which showed active S1P1 signalling in vivo. Moreover, ApoM-bound S1P, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom(-/-) mice developed more severe experimental autoimmune encephalomyelitis, characterized by increased lymphocytes in the central nervous system and breakdown of the blood-brain barrier. Thus, the ApoM-S1P-S1P1 signalling axis restrains the lymphocyte compartment and, subsequently, adaptive immune responses. Unique biological functions imparted by specific S1P chaperones could be exploited for novel therapeutic opportunities.
authors.affiliation: 1] Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA [2] Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Blaho
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Galvani
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Engelbrecht
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Liu
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Swendeman
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Mari
authors.initials: M
authors.lastname: Kono
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA.
authors.forename: May H
authors.initials: MH
authors.lastname: Han
authors.affiliation: 1] Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA [2] Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, New York 10065, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
mesh_terms: D000818:Animals; D001053:Apolipoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000075243:Apolipoproteins M; D001812:Blood-Brain Barrier / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation / Q000235:genetics; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008214:Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D054503:Lymphoid Progenitor Cells / Q000166:cytology / Q000378:metabolism; D038041:Lymphopoiesis; D008246:Lysophospholipids / Q000819:agonists / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics / Q000378:metabolism
chemical_list: C501623:ApoM protein, mouse; D001053:Apolipoproteins; D000075243:Apolipoproteins M; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine