Sphingosine 1-Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune Complex-Induced Vascular Injury.
Sphingosine 1-Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune Complex-Induced Vascular Injury.
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DOI：
10.1002/art.40558
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发表时间：
2018-11
期刊：
影响因子：
--
通讯作者：
Salmon JE
中科院分区：
文献类型：
--
作者：
Burg N;Swendeman S;Worgall S;Hla T;Salmon JE
Immune complex (IC) deposition activates neutrophils (PMN), increases vascular permeability and leads to organ damage in SLE and RA. The bioactive lipid sphingosine-1-phosphate (S1P), acting via S1P receptor 1 (S1P1), is a key regulator of endothelial cell (EC) barrier function. We hypothesized that augmenting EC integrity via S1P1 signaling would attenuate inflammatory injury mediated by ICs. In vitro barrier function was assessed in human umbilical vein endothelial cells (HUVECs) by Electric Cell-substrate Impedance Sensing (ECIS). Phosphorylation of myosin light chain2 (p-MLC2) and VE-Cadherin staining in HUVECs was assessed by immunofluorescence. Reverse Arthus reaction (RAR) in skin and lung was performed in mice with S1P1 deleted from ECs (ECKO) and mice treated with S1P1 agonists and antagonists. S1P1 agonists prevented loss of barrier function in HUVEC treated with IC-activated PMN. S1P1 ECKO and WT mice treated with S1P1 antagonists had amplified RAR, whereas specific S1P1 agonists attenuated skin and lung RAR in WT mice. ApoM-Fc, a novel S1P chaperone, mitigated EC cell barrier dysfunction induced by activated PMN in vitro and attenuated lung RAR. S1P1 agonists and ApoM-Fc markedly reduced p-MLC2 and disruption VE-Cadherin, manifestations of cell contraction and destabilization of adherence junctions, respectively, induced by activated PMN. S1P1 signaling in ECs modulates vascular responses to IC deposition. S1P1 agonists and ApoM-Fc enhance the EC barrier, limit leukocyte escape from capillaries, and provide protection from inflammatory injury. The S1P/S1P1 axis is a new target to attenuate tissue responses to IC deposition and mitigate end organ damage.
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影响因子：
7.3
作者：
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Hla T
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3.6
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