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.