Sphingosine-1-phosphate Lyase Deficiency Produces a Pro-inflammatory Response While Impairing Neutrophil Trafficking

Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2010; 286(9):7348-58. DOI: 10.1074/jbc.M110.171819
Source: PubMed


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.

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Available from: Weiping Chen, Dec 19, 2013
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    • " SPLFlox / Flox CreÀ . S1P ¼ sphingosine - 1 - phosphate ; PAS ¼ periodic acid – Schiff ' s reagent . succumb early in life to multiorgan failure ( Schmahl et al . 2007 ; Vogel et al . 2009 ) likely caused by excessive amounts of S1P accumulated in all tissues and associated with a major derailment of innate immune functions and lipid metabolism ( Allende et al . 2011 ; Bektas et al . 2010 ) . Obviously , this apparent target - mediated toxicity would prevent the use of S1P lyase inhibitors in case this toxicity would also occur in humans and under conditions where the enzyme would only be partially inhibited , as will likely be the case with pharma - ceutical inhibition . Therefore , we conducted a "
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    • "Thus, it is well established that the egress of T- and B-cells from lymphoid organs and their positioning in these organs are mediated by S1P signaling [8]–[11]. Moreover, S1P is involved in the modulation of several functions of natural killer cells, neutrophils, mast cells, macrophages and DCs [12]–[16]. S1P is produced from sphingosine by sphingosine kinases (SphK) from which two subtypes have been described, denoted as SphK1 and SphK2 [17], [18]. The complexity of S1P-mediated actions can be explained by the fact that it functions not only inside the cell but also acts as a ligand of G protein-coupled receptors (GPCRs), when it is secreted into the extracellular environment. "
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