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This study was designed to evaluate the effects of S1P\/S1PR on bone marrow-derived monocyte\/macrophage (BMM) migration in mouse models of cholestatic liver injury and identify the signaling pathway underlying this process. S1PR<jats:sub>1\u20133<\/jats:sub> expression in BMM was characterized by immunofluorescence, RT-PCR and Western blot. Cell migration was determined in Boyden chambers. <jats:italic>In vivo<\/jats:italic>, the chimera mice, which received BM transplants from EGFP-transgenic mice, received an operation of bile duct ligation (BDL) to induce liver injury with the administration of S1PR<jats:sub>2\/3<\/jats:sub> antagonists. The results showed that S1PR<jats:sub>1\u20133<\/jats:sub> were all expressed in BMMs. S1P exerted a powerful migratory action on BMMs via S1PR<jats:sub>2<\/jats:sub> and S1PR<jats:sub>3<\/jats:sub>. Furthermore, PTX and LY-294002 (PI3K inhibitor) prevented S1PR<jats:sub>2\/3<\/jats:sub>-mediated BMM migration and Rac1 activation by S1P was inhibited by JTE-013, CAY-10444 or LY294002. Administration of S1PR<jats:sub>2\/3<\/jats:sub> antagonists <jats:italic>in vivo<\/jats:italic> significantly reduced BMM recruitment in BDL-treated mice and attenuated hepatic inflammation and fibrosis. In conclusion, S1P\/S1PR<jats:sub>2\/3<\/jats:sub> system mediates BMM motility by PTX-PI3K-Rac1 signaling pathway, which provides new compelling information on the role of S1P\/S1PR in liver injury and opens new perspectives for the pharmacological treatment of hepatic fibrosis.<\/jats:p>","DOI":"10.1038\/srep13423","type":"journal-article","created":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T08:58:30Z","timestamp":1441097910000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Sphingosine 1-Phosphate Receptor 2 and 3 Mediate Bone Marrow-Derived Monocyte\/Macrophage Motility in Cholestatic Liver Injury in Mice"],"prefix":"10.1038","volume":"5","author":[{"given":"Le","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Mai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,9,1]]},"reference":[{"key":"BFsrep13423_CR1","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/nature12034","volume":"496","author":"TA Wynn","year":"2013","unstructured":"Wynn, T. 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