{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T20:10:50Z","timestamp":1793045450847,"version":"4.5.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T00:00:00Z","timestamp":1732838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>The disruption of blood-brain barrier (BBB) is associated with poor outcomes of TBI patients. Sphingosine-1-phosphate receptor 2 (S1pr2), a member of the G protein-coupled receptor family, is involved in endothelial activation and the regulation of vascular integrity. We hypothesized that the inhibition of S1pr2 may alleviate BBB disruption and explored potential underlying molecular mechanisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Lesion volumes were assessed utilizing Nissl staining; neurological outcomes were evaluated through a battery of neurobehavioral assessments; phenotype-associated proteins were scrutinized via Western blot analysis; levels of reactive oxygen species (ROS), neuronal apoptosis, and S1pr2 expression were determined using immunofluorescence staining. The impact of S1pr2 inhibition after TBI and its underlying mechanism were elucidated using the selective S1pr2 inhibitor JTE-013, the JNK phosphorylation inhibitor SP600125, and cellular models. Chip-qPCR was employed to further elucidate the binding sites of the transcription factor c-Jun.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The expression of S1pr2 significantly increased following TBI in mice. Pharmacological inhibition of S1pr2 alleviated secondary injury with reduced lesion volume, ROS generation, cerebral oedema, neurological deficits, and neuronal apoptosis; BBB disruption was also mitigated, accompanied by reduced degradation of tight junction proteins and decreased induction of matrix metalloproteinases-9 (MMP-9) post-TBI. Mechanistically, TBI induces an increase in S1pr2 specifically in endothelial cells, leading to the promotion of MMP-9 transactivation by enhancing JNK\/c-Jun signaling. This results in the degradation of tight junction proteins and increased BBB permeability. Through <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> Chip-qPCR experiments, we verified that AP-1a and AP-1b of MMP-9 promoter function as binding sites for phosphorylated c-Jun.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings identify a previously undisclosed role of S1pr2 in the pathophysiology of TBI. The S1pr2 inhibition presents a novel approach to alleviate BBB disruption after TBI through regulating the JNK\/c-Jun\/MMP-9 pathway.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2024.1448570","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T04:35:22Z","timestamp":1732854922000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["Overexpression of endothelial S1pr2 promotes blood\u2013brain barrier disruption via JNK\/c-Jun\/MMP-9 pathway after traumatic brain injury in both in vivo and in vitro models"],"prefix":"10.3389","volume":"15","author":[{"given":"Hongbo","family":"Cheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijiao","family":"Men","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqing","family":"An","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiegang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gengshen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoliang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guozhu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2350","DOI":"10.3390\/cells9112350","article-title":"Alarmins and c-jun N-terminal kinase (JNK) signaling in neuroinflammation","volume":"9","author":"Anfinogenova","year":"2020","journal-title":"Cells"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1622","DOI":"10.1210\/en.2006-1068","article-title":"p38 mitogen-activated protein kinase mediates palmitate-induced apoptosis but not inhibitor of nuclear factor-kappaB degradation in human coronary artery endothelial cells","volume":"148","author":"Chai","year":"2007","journal-title":"Endocrinology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1007\/s12035-013-8538-z","article-title":"Mmp-9 inhibition: a therapeutic strategy in ischemic stroke","volume":"49","author":"Chaturvedi","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"eabn0067","DOI":"10.1126\/sciadv.abn0067","article-title":"Structure of S1PR2-heterotrimeric G(13) signaling complex","volume":"8","author":"Chen","year":"2022","journal-title":"Sci. Adv."},{"key":"B5","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1038\/aps.2018.27","article-title":"Targeting RNS\/caveolin-1\/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery","volume":"39","author":"Chen","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"B6","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1016\/j.jtcme.2020.03.008","article-title":"The role of nutraceuticals as a complementary therapy against various neurodegenerative diseases: a mini-review","volume":"10","author":"Chiu","year":"2020","journal-title":"J. Tradit. Complement. Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1164\/rccm.200509-1527OC","article-title":"Signal transduction pathways of tumor necrosis factor--mediated lung injury induced by ozone in mice","volume":"175","author":"Cho","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.wneu.2013.01.015","article-title":"The potential utility of blood-derived biochemical markers as indicators of early clinical trends following severe traumatic brain injury","volume":"81","author":"DeFazio","year":"2014","journal-title":"World Neurosurg."},{"key":"B9","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.tins.2020.12.004","article-title":"Bidirectional brain-systemic interactions and outcomes after TBI","volume":"44","author":"Faden","year":"2021","journal-title":"Trends Neurosci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s13072-018-0215-z","article-title":"Sporadic DUX4 expression in FSHD myocytes is associated with incomplete repression by the PRC2 complex and gain of H3K9 acetylation on the contracted D4Z4 allele","volume":"11","author":"Haynes","year":"2018","journal-title":"Epigenetics Chromatin"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1161\/CIRCULATIONAHA.114.013003","article-title":"Vascular signal transducer and activator of transcription-3 promotes angiogenesis and neuroplasticity long-term after stroke","volume":"131","author":"Hoffmann","year":"2015","journal-title":"Circulation"},{"key":"B12","doi-asserted-by":"publisher","first-page":"286","DOI":"10.7150\/ijbs.15171","article-title":"BEX2 promotes tumor proliferation in colorectal cancer","volume":"13","author":"Hu","year":"2017","journal-title":"Int. J. Biol. Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.1016\/j.bcp.2010.02.003","article-title":"Suppression of PMA-induced tumor cell invasion by dihydroartemisinin via inhibition of PKCalpha\/Raf\/MAPKs and NF-kappaB\/AP-1-dependent mechanisms","volume":"79","author":"Hwang","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"106720","DOI":"10.1016\/j.phrs.2023.106720","article-title":"An MMP-9 exclusive neutralizing antibody attenuates blood-brain barrier breakdown in mice with stroke and reduces stroke patient-derived MMP-9 activity","volume":"190","author":"Ji","year":"2023","journal-title":"Pharmacol. Res."},{"key":"B15","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1007\/s00401-018-1824-0","article-title":"Mechanical disruption of the blood-brain barrier following experimental concussion","volume":"135","author":"Johnson","year":"2018","journal-title":"Acta Neuropathol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"7893","DOI":"10.1038\/ncomms8893","article-title":"Critical role of sphingosine-1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke","volume":"6","author":"Kim","year":"2015","journal-title":"Nat. Commun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.bbrc.2019.02.047","article-title":"Sphingosine-1-phosphate receptor 1 promotes neointimal hyperplasia in a mouse model of carotid artery injury","volume":"511","author":"Kitano","year":"2019","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"B18","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1007\/s00011-019-01217-z","article-title":"Bazedoxifene protects cerebral autoregulation after traumatic brain injury and attenuates impairments in blood-brain barrier damage: involvement of anti-inflammatory pathways by blocking MAPK signaling","volume":"68","author":"Lan","year":"2019","journal-title":"Inflamm. Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1128\/IAI.05837-11","article-title":"Two strikingly different signaling pathways are induced by meningococcal type IV pili on endothelial and epithelial cells","volume":"80","author":"Lecuyer","year":"2012","journal-title":"Infect. Immun."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1089\/neu.2013.3251","article-title":"Therapeutic effects of pharmacologically induced hypothermia against traumatic brain injury in mice","volume":"31","author":"Lee","year":"2014","journal-title":"J. Neurotrauma"},{"key":"B21","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.expneurol.2011.12.016","article-title":"Effects of aging on blood brain barrier and matrix metalloproteases following controlled cortical impact in mice","volume":"234","author":"Lee","year":"2012","journal-title":"Exp. Neurol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3169","DOI":"10.1093\/eurheartj\/ehaa207","article-title":"Adipocyte fatty acid-binding protein exacerbates cerebral ischaemia injury by disrupting the blood-brain barrier","volume":"41","author":"Liao","year":"2020","journal-title":"Eur. Heart J."},{"key":"B23","doi-asserted-by":"publisher","first-page":"e11407","DOI":"10.1016\/j.heliyon.2022.e11407","article-title":"Didang Tang inhibits intracerebral hemorrhage-induced neuronal injury via ASK1\/MKK7\/JNK signaling pathway, network pharmacology-based analyses combined with experimental validation","volume":"8","author":"Lu","year":"2022","journal-title":"Heliyon"},{"key":"B24","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1007\/s11011-014-9550-3","article-title":"Ablation of matrix metalloproteinase-9 gene decreases cerebrovascular permeability and fibrinogen deposition post traumatic brain injury in mice","volume":"30","author":"Muradashvili","year":"2015","journal-title":"Metab. Brain Dis."},{"key":"B25","doi-asserted-by":"publisher","first-page":"603","DOI":"10.1038\/s42003-020-01343-z","article-title":"PRL-2 phosphatase is required for vascular morphogenesis and angiogenic signaling","volume":"3","author":"Poulet","year":"2020","journal-title":"Commun. Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3530","DOI":"10.1002\/jnr.22510","article-title":"Increase in blood-brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury","volume":"88","author":"Readnower","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1089\/neu.2014.3847","article-title":"Is traumatic brain injury associated with reduced inter-hemispheric functional connectivity? A study of large-scale resting state networks following traumatic brain injury","volume":"33","author":"Rigon","year":"2016","journal-title":"J. Neurotrauma"},{"key":"B28","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.neuron.2019.06.002","article-title":"Cerebral microvascular injury: a potentially treatable endophenotype of traumatic brain injury-induced neurodegeneration","volume":"103","author":"Sandsmark","year":"2019","journal-title":"Neuron"},{"key":"B29","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1016\/j.nbd.2018.11.018","article-title":"Inactivation of sphingosine-1-phosphate receptor 2 (S1PR2) decreases demyelination and enhances remyelination in animal models of multiple sclerosis","volume":"124","author":"Seyedsadr","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"B30","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1186\/s12974-018-1227-0","article-title":"Inflammation and blood-brain barrier breach remote from the primary injury following neurotrauma","volume":"15","author":"Smith","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"B31","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.apsb.2014.11.002","article-title":"Ameliorating effects of traditional Chinese medicine preparation, Chinese materia medica and active compounds on ischemia\/reperfusion-induced cerebral microcirculatory disturbances and neuron damage","volume":"5","author":"Sun","year":"2015","journal-title":"Acta Pharm. Sin. B"},{"key":"B32","doi-asserted-by":"publisher","first-page":"105642","DOI":"10.1016\/j.neuint.2023.105642","article-title":"Matrix Metalloproteinase-9 inhibitors as therapeutic drugs for traumatic brain injury","volume":"172","author":"Sunny","year":"2024","journal-title":"Neurochem. Int."},{"key":"B33","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1089\/neu.2012.2647","article-title":"Selective inhibition of alpha\/beta-hydrolase domain 6 attenuates neurodegeneration, alleviates blood brain barrier breakdown, and improves functional recovery in a mouse model of traumatic brain injury","volume":"30","author":"Tchantchou","year":"2013","journal-title":"J. Neurotrauma"},{"key":"B34","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1038\/s41467-017-01562-9","article-title":"Transcribed ultraconserved region 339 promotes carcinogenesis by modulating tumor suppressor microRNAs","volume":"8","author":"Vannini","year":"2017","journal-title":"Nat. Commun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/s41419-022-04794-w","article-title":"Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis","volume":"13","author":"Wang B.","year":"2022","journal-title":"Cell. Death Dis."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2967","DOI":"10.3390\/molecules27092967","article-title":"A calixarene assembly strategy of combined anti-neuroinflammation and drug delivery functions for traumatic brain injury therapy","volume":"27","author":"Wang C.","year":"2022","journal-title":"Molecules"},{"key":"B37","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1186\/1423-0127-18-94","article-title":"Topical application of marine briarane-type diterpenes effectively inhibits 12-O-tetradecanoylphorbol-13-acetate-induced inflammation and dermatitis in murine skin","volume":"18","author":"Wei","year":"2011","journal-title":"J. Biomed. Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1177\/0271678X20904687","article-title":"Tight junctions in the blood-brain barrier promote edema formation and infarct size in stroke - ambivalent effects of sealing proteins","volume":"41","author":"Winkler","year":"2021","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1002\/hep.22087","article-title":"Cytochrome P4502E1 sensitizes to tumor necrosis factor alpha-induced liver injury through activation of mitogen-activated protein kinases in mice","volume":"47","author":"Wu","year":"2008","journal-title":"Hepatology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"204","DOI":"10.3390\/antiox9030204","article-title":"MiR155-5p inhibits cell migration and oxidative stress in vascular smooth muscle cells of spontaneously hypertensive rats","volume":"9","author":"Wu","year":"2020","journal-title":"Antioxidants (Basel)"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1172334","DOI":"10.3389\/fimmu.2023.1172334","article-title":"Pterostilbene attenuates microglial inflammation and brain injury after intracerebral hemorrhage in an OPA1-dependent manner","volume":"14","author":"Wu","year":"2023","journal-title":"Front. Immunol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"569802","DOI":"10.3389\/fphar.2020.569802","article-title":"Sphingosine 1-phosphate induces cyclooxygenase-2\/prostaglandin E2 expression via pkc\u03b1-dependent mitogen-activated protein kinases and NF-\u03baB cascade in human cardiac fibroblasts","volume":"11","author":"Yang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"46304","DOI":"10.1038\/srep46304","article-title":"Sevoflurane decreases self-renewal capacity and causes c-Jun N-terminal kinase-mediated damage of rat fetal neural stem cells","volume":"7","author":"Yang","year":"2017","journal-title":"Sci. Rep."},{"key":"B44","doi-asserted-by":"publisher","first-page":"677810","DOI":"10.3389\/fphar.2021.677810","article-title":"Salidroside inhibits CCl(4)-induced liver fibrosis in mice by reducing activation and migration of HSC induced by liver sinusoidal endothelial cell-derived exosomal SphK1","volume":"12","author":"Ye","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1182\/blood-2012-11-467191","article-title":"Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute vascular inflammation","volume":"122","author":"Zhang","year":"2013","journal-title":"Blood"},{"key":"B46","doi-asserted-by":"publisher","first-page":"5755","DOI":"10.3390\/molecules27185755","article-title":"Recombinant human annexin A5 alleviated traumatic-brain-injury induced intestinal injury by regulating the Nrf2\/HO-1\/HMGB1 pathway","volume":"27","author":"Zhang","year":"2022","journal-title":"Molecules"},{"key":"B47","doi-asserted-by":"publisher","first-page":"650770","DOI":"10.3389\/fphar.2021.650770","article-title":"Investigation of the multi-target mechanism of guanxin-shutong capsule in cerebrovascular diseases: a systems pharmacology and experimental assessment","volume":"12","author":"Zhang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B48","doi-asserted-by":"publisher","first-page":"943","DOI":"10.14336\/AD.2021.1029","article-title":"Blocking C3d(+)\/GFAP(+) A1 astrocyte conversion with semaglutide attenuates blood-brain barrier disruption in mice after ischemic stroke","volume":"13","author":"Zhang Q","year":"2022","journal-title":"Aging Dis."},{"key":"B49","doi-asserted-by":"publisher","first-page":"16088","DOI":"10.18632\/aging.203136","article-title":"High glucose exacerbates neuroinflammation and apoptosis at the intermediate stage after post-traumatic brain injury","volume":"13","author":"Zhang","year":"2021","journal-title":"Aging (Albany NY)"},{"key":"B50","doi-asserted-by":"publisher","first-page":"5172","DOI":"10.7150\/thno.71585","article-title":"Endothelial S1pr2 regulates post-ischemic angiogenesis via AKT\/eNOS signaling pathway","volume":"12","author":"Zhou","year":"2022","journal-title":"Theranostics"}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1448570\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T04:35:25Z","timestamp":1732854925000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1448570\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,29]]},"references-count":50,"alternative-id":["10.3389\/fphar.2024.1448570"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1448570","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,29]]},"article-number":"1448570"}}