{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:38:09Z","timestamp":1790267889369,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2018,10,26]],"date-time":"2018-10-26T00:00:00Z","timestamp":1540512000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL\u2010135821"],"award-info":[{"award-number":["HL\u2010135821"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004856","name":"New York State Department of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004856","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2018,11]]},"abstract":"Objective<\/jats:title>Immune complex (IC<\/jats:styled-content>) deposition activates polymorphonuclear neutrophils (PMN<\/jats:styled-content>s), increases vascular permeability, and leads to organ damage in systemic lupus erythematosus and rheumatoid arthritis. The bioactive lipid sphingosine 1\u2010phosphate (S1P), acting via S1P receptor 1 (S1P1<\/jats:sub>), is a key regulator of endothelial cell (EC<\/jats:styled-content>) barrier function. This study was undertaken to investigate whether augmenting EC<\/jats:styled-content> integrity via S1P1<\/jats:sub> signaling attenuates inflammatory injury mediated by IC<\/jats:styled-content>s.<\/jats:p><\/jats:sec>Methods<\/jats:title>In vitro barrier function was assessed in human umbilical vein endothelial cells (HUVEC<\/jats:styled-content>s) by electrical cell\u2010substrate impedance sensing. Phosphorylation of myosin light chain 2 (p\u2013MLC<\/jats:styled-content>\u20102) and VE<\/jats:styled-content>\u2010cadherin staining in HUVEC<\/jats:styled-content>s were assessed by immunofluorescence. A reverse Arthus reaction (RAR<\/jats:styled-content>) was induced in the skin and lungs of mice with S1P1<\/jats:sub> deleted from EC<\/jats:styled-content>s (S1P1<\/jats:sub> EC<\/jats:styled-content>\u2010knockout [ECKO<\/jats:styled-content>] mice) and mice treated with S1P1<\/jats:sub> agonists and antagonists.<\/jats:p><\/jats:sec>Results<\/jats:title>S1P1<\/jats:sub> agonists prevented loss of barrier function in HUVEC<\/jats:styled-content>s treated with IC<\/jats:styled-content>\u2010activated PMN<\/jats:styled-content>s. S1P1<\/jats:sub> ECKO<\/jats:styled-content> and wild\u2010type (WT<\/jats:styled-content>) mice treated with S1P1<\/jats:sub> antagonists had amplified RAR<\/jats:styled-content>, whereas specific S1P1<\/jats:sub> agonists attenuated skin and lung RAR<\/jats:styled-content> in WT<\/jats:styled-content> mice. ApoM\u2010Fc, a novel S1P chaperone, mitigated EC<\/jats:styled-content> cell barrier dysfunction induced by activated PMN<\/jats:styled-content>s in\u00a0vitro and attenuated lung RAR<\/jats:styled-content>. Expression levels of p\u2013MLC<\/jats:styled-content>\u20102 and disruption of VE<\/jats:styled-content>\u2010cadherin, each representing manifestations of cell contraction and destabilization of adherens junctions, respectively, that were induced by activated PMN<\/jats:styled-content>s, were markedly reduced by treatment with S1P1<\/jats:sub> agonists and ApoM\u2010Fc.<\/jats:p><\/jats:sec>Conclusion<\/jats:title>Our findings indicate that S1P1<\/jats:sub> signaling in EC<\/jats:styled-content>s modulates vascular responses to IC<\/jats:styled-content> deposition. S1P1<\/jats:sub> agonists and ApoM\u2010Fc enhance the EC<\/jats:styled-content> barrier, limit leukocyte escape from capillaries, and provide protection against inflammatory injury. The S1P\/S1P1<\/jats:sub> axis is a newly identified target to attenuate tissue responses to IC<\/jats:styled-content> deposition and mitigate end\u2010organ damage.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.40558","type":"journal-article","created":{"date-parts":[[2018,5,21]],"date-time":"2018-05-21T05:36:23Z","timestamp":1526880983000},"page":"1879-1889","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":86,"title":["Sphingosine 1\u2010Phosphate Receptor 1 Signaling Maintains Endothelial Cell Barrier Function and Protects Against Immune\u00a0Complex\u2013Induced Vascular Injury"],"prefix":"10.1002","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1944-8086","authenticated-orcid":false,"given":"Nathalie","family":"Burg","sequence":"first","affiliation":[{"name":"Hospital for Special Surgery and Weill Cornell Medicine New York New 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