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Therapeutic Value of S1PR3 Signaling in Pre-Clinical Sepsis
Markus H. Gräler 1, Anke C. Ziegler 11 Department of Anesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and Center for Molecular Biomedicine (CMB), Jena University Hospital, Hans-Knöll-Str. 2, 07745 Jena, Germany
Sepsis is a life-threatening organ dysfunction caused by a dysregulated immune response to infection. The only causative treatment available today are anti-infectives. A major problem is that anti-infectives are most effective in the early stage of an infection and do not work well at later time points, meaning that sepsis patients requiring intensive care do not benefit anymore from anti-infective treatment. For these most critical cases supportive treatment is the only available option. We recently demonstrated that preventive treatment with sphingosine 1-phosphate (S1P) lyase inhibitors was able to increase survival of mice that were challenged with polymicrobial peritoneal contamination and infection (PCI), which is an established model for experimental sepsis. This pro-survival effect was completely abolished in S1P receptor type 3 (S1PR3) deficient mice, indicating that S1PR3 has a central role for the observed pre-conditioning effect of S1P lyase inhibition. Here, we demonstrate that both, S1P lyase inhibition and S1PR3 activation also have therapeutic value in infected mice when applied 6 h after infection. Treated mice recovered from the septic insult considerably faster than untreated animals with decreased secretion of inflammatory cytokines IL-6, MCP-1, TNF-alpha and IL-10 and decreased protein leakage in bronchoalveolar lavage fluid (BALF). Notably, the bacterial load in lung, liver and whole blood was not different between treated and untreated mice after infection. S1P lyase inhibition and S1PR3 activation were not effective in S1PR3 deficient mice treated 6 h after infection. While the exact molecular mechanisms underlying the survival benefit after S1P lyase inhibition and S1PR3 activation in infected mice are still under investigation, S1PR3 appears as an attractive target for sepsis treatment.