Article

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

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.

Download full-text

Full-text

Available from: Weiping Chen, Dec 19, 2013
  • Source
    • " 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 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sphingosine-1-phosphate (S1P) lyase is considered as a drug target in autoimmune diseases based on the protective effect of reducing activity of the enzyme in animal models of inflammation. Since S1P lyase deficiency in mice causes a severe, lethal phenotype, it was of interest to investigate any pathological alterations associated with only partially reduced activity of S1P lyase as may be encountered upon pharmacological inhibition. Both genetic reduction of S1P lyase activity in mice and inhibition of S1P lyase with a low-molecular-weight compound in rats consistently resulted in podocyte-based kidney toxicity, which is the most severe finding. In addition, skin irritation and platelet activation were observed in both instances. The similarity of the findings in both the genetic model and the pharmacological study supports the value of analyzing inducible partially target-deficient mice for safety assessment. If the findings described in rodents translate to humans, target-related toxicity, particularly podocyte dysfunction, may limit chronic systemic treatment of autoimmune diseases with S1P lyase inhibitors. Furthermore, partial deficiency or inhibition of S1P lyase appears to provide an in vivo rodent model to enable studies on the mechanism of podocyte dysfunction. © 2015 by The Author(s).
    Full-text · Article · Jan 2015 · Toxicologic Pathology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P(2) receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P(2) not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions.
    Full-text · Article · Nov 2012 · PLoS ONE
  • [Show abstract] [Hide abstract]
    ABSTRACT: The bioactive signaling molecule D-erythro-sphingosine-1-phosphate (S1P) is irreversibly degraded by the enzyme S1P lyase (SPL). The reaction of SPL with C18-S1P generates ethanolamine phosphate and a long-chain fatty aldehyde, trans-2-hexadecenal. Modulation of SPL expression in cells and organisms produces significant phenotypes, most of which have been attributed to corresponding changes in S1P-dependent signaling. However, the physiological functions of SPL products are not well understood. In the present study, we explored the biological activities of trans-2-hexadecenal in human and murine cells. We demonstrate that trans-2-hexadecenal causes cytoskeletal reorganization leading to cell rounding, detachment and eventual cell death by apoptosis in multiple cell types, including HEK293T, NIH3T3 and HeLa cells. Trans-2-hexadecenal stimulated a signaling pathway involving MLK3 and the respective phosphorylation of MKK4/7 and JNK, whereas ERK, AKT and p38 were unaffected. Trans-2-hexadecenal-induced apoptosis was accompanied by activation of downstream targets of JNK including c-Jun phosphorylation, cytochrome c release, Bax activation, Bid cleavage and increased translocation of Bim into mitochondria. The antioxidant N-acetylcysteine prevented JNK activation by trans-2-hexadecenal. Further, inhibition of JNK abrogated the cytoskeletal changes and apoptosis caused by trans-2-hexadecenal, whereas Rac1 and RhoA were not involved. In conclusion, our studies provide a new paradigm of sphingolipid signaling by demonstrating for the first time that S1P metabolism generates a bioactive product that induces cellular effects through oxidant stress-dependent MAP kinase cell signaling.
    No preview · Article · Mar 2011 · Cellular Signalling
Show more