title: Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking.
abstract: Sphingosine-1-phosphate (S1P) lyase catalyzes the degradation of S1P, a potent signaling lysosphingolipid. Mice with an inactive S1P lyase gene are impaired in the capacity to degrade S1P, resulting in highly elevated S1P levels. These S1P lyase-deficient mice have low numbers of lymphocytes and high numbers of neutrophils in their blood. We found that the S1P lyase-deficient mice exhibited features of an inflammatory response including elevated levels of pro-inflammatory cytokines and an increased expression of genes in liver associated with an acute-phase response. However, the recruitment of their neutrophils into inflamed tissues was impaired and their neutrophils were defective in migration to chemotactic stimulus. The IL-23/IL-17/granulocyte-colony stimulating factor (G-CSF) cytokine-controlled loop regulating neutrophil homeostasis, which is dependent on neutrophil trafficking to tissues, was disturbed in S1P lyase-deficient mice. Deletion of the S1P4 receptor partially decreased the neutrophilia and inflammation in S1P lyase-deficient mice, implicating S1P receptor signaling in the phenotype. Thus, a genetic block in S1P degradation elicits a pro-inflammatory response but impairs neutrophil migration from blood into tissues.
authors.affiliation: Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Allende
authors.forename: Meryem
authors.initials: M
authors.lastname: Bektas
authors.forename: Bridgin G
authors.initials: BG
authors.lastname: Lee
authors.forename: Eliana
authors.initials: E
authors.lastname: Bonifacino
authors.forename: Jiman
authors.initials: J
authors.lastname: Kang
authors.forename: Galina
authors.initials: G
authors.lastname: Tuymetova
authors.forename: WeiPing
authors.initials: W
authors.lastname: Chen
authors.forename: Julie D
authors.initials: JD
authors.lastname: Saba
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
mesh_terms: D000209:Acute-Phase Proteins / Q000276:immunology; D000446:Aldehyde-Lyases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D006410:Hematopoiesis / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008246:Lysophospholipids / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000276:immunology / Q000378:metabolism
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine