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Open AccessArticle

Inflammatory Conditions Disrupt Constitutive Endothelial Cell Barrier Stabilization by Alleviating Autonomous Secretion of Sphingosine 1-Phosphate

1
Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, 07740 Jena, Germany
2
Center for Molecular Biomedicine, Jena University Hospital, 07745 Jena, Germany
3
Center for Sepsis Control and Care, Jena University Hospital, 07740 Jena, Germany
4
Leibniz Institute on Aging—Fritz Lipmann Institute, 07745 Jena, Germany
5
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA
6
Institute of Molecular Cell Biology, Jena University Hospital, 07745 Jena, Germany
*
Author to whom correspondence should be addressed.
Cells 2020, 9(4), 928; https://doi.org/10.3390/cells9040928
Received: 6 March 2020 / Revised: 30 March 2020 / Accepted: 7 April 2020 / Published: 10 April 2020
(This article belongs to the Special Issue Sphingolipids: From Pathology to Therapeutic Perspectives)
The breakdown of the endothelial cell (EC) barrier contributes significantly to sepsis mortality. Sphingosine 1-phosphate (S1P) is one of the most effective EC barrier-stabilizing signaling molecules. Stabilization is mainly transduced via the S1P receptor type 1 (S1PR1). Here, we demonstrate that S1P was autonomously produced by ECs. S1P secretion was significantly higher in primary human umbilical vein endothelial cells (HUVEC) compared to the endothelial cell line EA.hy926. Constitutive barrier stability of HUVEC, but not EA.hy926, was significantly compromised by the S1PR1 antagonist W146 and by the anti-S1P antibody Sphingomab. HUVEC and EA.hy926 differed in the expression of the S1P-transporter Spns2, which allowed HUVEC, but not EA.hy926, to secrete S1P into the extracellular space. Spns2 deficient mice showed increased serum albumin leakage in bronchoalveolar lavage fluid (BALF). Lung ECs isolated from Spns2 deficient mice revealed increased leakage of fluorescein isothiocyanate (FITC) labeled dextran and decreased resistance in electric cell-substrate impedance sensing (ECIS) measurements. Spns2 was down-regulated in HUVEC after stimulation with pro-inflammatory cytokines and lipopolysaccharides (LPS), which contributed to destabilization of the EC barrier. Our work suggests a new mechanism for barrier integrity maintenance. Secretion of S1P by EC via Spns2 contributed to constitutive EC barrier maintenance, which was disrupted under inflammatory conditions via the down-regulation of the S1P-transporter Spns2. View Full-Text
Keywords: S1P receptor; inflammation; S1P transporter; spinster homolog 2; barrier dysfunction S1P receptor; inflammation; S1P transporter; spinster homolog 2; barrier dysfunction
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MDPI and ACS Style

Jeya Paul, J.; Weigel, C.; Müller, T.; Heller, R.; Spiegel, S.; Gräler, M.H. Inflammatory Conditions Disrupt Constitutive Endothelial Cell Barrier Stabilization by Alleviating Autonomous Secretion of Sphingosine 1-Phosphate. Cells 2020, 9, 928.

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