title: Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in LDL-receptor deficient mice.
abstract: OBJECTIVE
  Altered sphingosine 1-phosphate (S1P) homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we investigated the impact of hematopoietic S1P lyase (Sgpl1(-/-)) deficiency on leukocyte subsets relevant to atherosclerosis.
  
  
  RESULTS
  LDL receptor deficient mice that were transplanted with Sgpl1(-/-) bone marrow showed disrupted S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to controls. Remarkably however, Sgpl1(-/-) chimeras displayed mild monocytosis, due to impeded stromal retention and myelopoiesis, and plasma cytokine and macrophage expression patterns, that were largely compatible with classical macrophage activation. Collectively these two phenotypic features of Sgpl1 deficiency culminated in diminished atherogenic response.
  
  
  CONCLUSIONS
  Here we not only firmly establish the critical role of hematopoietic S1P lyase in controlling S1P levels and T cell trafficking in blood and lymphoid tissue, but also identify leukocyte Sgpl1 as critical factor in monocyte macrophage differentiation and function. Its, partly counterbalancing, pro- and anti-inflammatory activity spectrum imply that intervention in S1P lyase function in inflammatory disorders such as atherosclerosis should be considered with caution.
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: Bot
authors.forename: Paul P
authors.initials: PP
authors.lastname: Van Veldhoven
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.forename: Jason
authors.initials: J
authors.lastname: Johnson
authors.forename: Niels
authors.initials: N
authors.lastname: Nijstad
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Van Santbrink
authors.forename: Marijke M
authors.initials: MM
authors.lastname: Westra
authors.forename: Gerd
authors.initials: G
authors.lastname: Van Der Hoeven
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Georg
authors.initials: G
authors.lastname: Varga
authors.forename: Uwe J F
authors.initials: UJ
authors.lastname: Tietge
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: Van Berkel
authors.forename: Jerzy-Roch
authors.initials: JR
authors.lastname: Nofer
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000446:Aldehyde-Lyases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000201:enzymology; D002454:Cell Differentiation; D005260:Female; D006410:Hematopoiesis; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000201:enzymology / Q000276:immunology; D008246:Lysophospholipids / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D013154:Spleen / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D011973:Receptors, LDL; C060506:sphingosine 1-phosphate; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine