Modulating sphingosine 1‐phosphate signaling with DOP or FTY720 alleviates vascular and immune defects in mouse sepsis

• Published in: European journal of immunology 2016-12, Vol.46 (12), p.2767-2777
• Main Authors: Hemdan, Nasr Y. A., Weigel, Cynthia, Reimann, Christina‐Maria, Gräler, Markus H.
• Format: Article
• Language: English
• Subjects: Animals; Capillary Permeability - drug effects; Cells, Cultured; Cytokine; Cytokines - metabolism; Endothelial barrier; Fingolimod Hydrochloride - therapeutic use; Immunomodulation; Leukocytes; Lymphopenia; Lysophospholipids - metabolism; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Peritoneal contamination and infection; Phosphoric Monoester Hydrolases - metabolism; Pyridoxine - analogs & derivatives; Pyridoxine - therapeutic use; Receptors, Lysosphingolipid - metabolism; Rodents; Sepsis; Sepsis - drug therapy; Sepsis - immunology; Signal Transduction; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Vascular Endothelial Growth Factor A - blood
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201646417

Sepsis is a systemic inflammatory response to pathogens and a leading cause of hospital related mortality worldwide. Sphingosine 1‐phosphate (S1P) regulates multiple cellular processes potentially involved in the pathogenesis of sepsis, including antigen presentation, lymphocyte egress, and maintenance of vascular integrity. We thus explored the impact of manipulating S1P signaling in experimental polymicrobial sepsis in mice. Administration of 4‐deoxypyridoxine (DOP), an inhibitor of the S1P‐degrading enzyme S1P‐lyase, or of the sphingosine analog FTY720 that serves as an S1P receptor agonist after phosphorylation ameliorated morbidity, improved recovery from sepsis in surviving mice, and reduced sepsis‐elicited hypothermia and body weight loss. Treated mice developed lymphopenia, leading to an accumulation of lymphocytes in peripheral lymph nodes, and reduced bacterial burden in liver, but not in blood. Sepsis‐induced upregulation of mRNA expression of cytokines in spleen remained unchanged, but reduction of IL‐6, TNF‐α, MCP‐1, and IL‐10 in plasma was evident. DOP and FTY720 treatment significantly reduced levels of Evans blue leakage from blood into liver and lung, decreased hematocrit values, and lowered plasma levels of VEGF‐A in septic mice. Collectively, our results indicate that modulation of S1P signaling showed a protective phenotype in experimental sepsis by modulating vascular and immune functions. Mice challenged with peritoneal contamination and infection as an experimental sepsis model were treated with the SGPL1 inhibitor DOP leading to increased S1P levels in lymphoid organs, or with the immune modulator FTY720, which activates S1P receptors after phosphorylation. Resultant vascular and immune effects like modulation of the cytokine profile, induction of lymphopenia, and modulation of the vascular endothelial barrier consequently improved sepsis outcome.