Publication Date:
2015-06-09
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506268/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506268/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blaho, Victoria A -- Galvani, Sylvain -- Engelbrecht, Eric -- Liu, Catherine -- Swendeman, Steven L -- Kono, Mari -- Proia, Richard L -- Steinman, Lawrence -- Han, May H -- Hla, Timothy -- F32 CA14211/CA/NCI NIH HHS/ -- F32 CA142117/CA/NCI NIH HHS/ -- HL67330/HL/NHLBI NIH HHS/ -- HL70694/HL/NHLBI NIH HHS/ -- HL89934/HL/NHLBI NIH HHS/ -- P01 HL070694/HL/NHLBI NIH HHS/ -- P20 RR017677/RR/NCRR NIH HHS/ -- P30 CA138313/CA/NCI NIH HHS/ -- R01 HL089934/HL/NHLBI NIH HHS/ -- R37 HL067330/HL/NHLBI NIH HHS/ -- Z01 DK056014-02/Intramural NIH HHS/ -- Z01 DK056015-01/Intramural NIH HHS/ -- England -- Nature. 2015 Jul 16;523(7560):342-6. doi: 10.1038/nature14462. Epub 2015 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA. ; Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA. ; Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26053123" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Apolipoproteins/deficiency/genetics/*metabolism
;
Blood-Brain Barrier/pathology
;
Cell Movement
;
Cell Proliferation/genetics
;
Central Nervous System/immunology/metabolism/*pathology
;
Encephalomyelitis, Autoimmune,
;
Experimental/genetics/immunology/metabolism/pathology
;
Female
;
Fingolimod Hydrochloride/pharmacology
;
Hematopoietic Stem Cells/cytology/metabolism
;
Inflammation/immunology/metabolism/pathology
;
Lipoproteins, HDL/*metabolism
;
Lymphocytes/*cytology/immunology/*metabolism
;
Lymphoid Progenitor Cells/cytology/metabolism
;
*Lymphopoiesis
;
Lysophospholipids/agonists/blood/genetics/*metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
Protein Binding
;
Receptors, Lysosphingolipid/metabolism
;
Signal Transduction
;
Sphingosine/agonists/*analogs & derivatives/blood/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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