{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T21:08:46Z","timestamp":1784581726780,"version":"3.55.0"},"reference-count":43,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2017,8,21]],"date-time":"2017-08-21T00:00:00Z","timestamp":1503273600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15K09711 to K.M."],"award-info":[{"award-number":["15K09711 to K.M."]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15K09499 to K.Y"],"award-info":[{"award-number":["15K09499 to K.Y"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2017,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Exaggerated maternal immune responses must be strictly controlled to ensure a successful pregnancy. Neutrophil extracellular traps (NETs) have recently been implicated as a potential mechanism for promoting inflammation in pregnancy\u2010related disorders. In this study, we demonstrated that NETs play a key role in the pathogenesis of sphingosine kinase (Sphk)\u2010mediated pregnancy loss. Perturbing the sphingolipid pathway by disrupting\n                    <jats:italic>Sphk<\/jats:italic>\n                    genes during pregnancy led to excessive NET formation exclusively at the fetomaternal interface and early fetal death. Neutrophils that formed NETs were characterized by histone hypercitrullination and peptidylarginine deiminase 4 (PAD4) overexpression. In addition, thrombus formation was enhanced in the decidua, but not in the plasma, of\n                    <jats:italic>Sphk<\/jats:italic>\n                    \u2010deficient mice. Blocking NET formation with a PAD4 inhibitor protected\n                    <jats:italic>Sphk<\/jats:italic>\n                    \u2010deficient mice from pregnancy loss. The PAD4 inhibition significantly reduced the expression of hypercitrullinated histone in neutrophils and ameliorated vascular injury in the decidua of\n                    <jats:italic>Sphk<\/jats:italic>\n                    \u2010deficient mice. Moreover, NET formation was induced in human neutrophils stimulated with Sphk\u2010deficient human decidual cells. Together, these findings indicate that targeting NETs might be a novel therapeutic strategy to treat idiopathic pregnancy loss in humans.\u2014Mizugishi, K., Yamashita, K. Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase\u2013deficient mice on 129Sv\/C57BL\/6 background. FASEB J. 31, 5577\u20135591 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700399rr","type":"journal-article","created":{"date-parts":[[2017,8,21]],"date-time":"2017-08-21T20:40:21Z","timestamp":1503348021000},"page":"5577-5591","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Neutrophil extracellular traps are critical for pregnancy loss in sphingosine kinase\u2013deficient mice on 129Sv\/C57BL\/6 background"],"prefix":"10.1096","volume":"31","author":[{"given":"Kiyomi","family":"Mizugishi1","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology Kyoto University Hospital Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kouhei","family":"Yamashita","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Kyoto University Hospital Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,8,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI76369"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-020711-075011"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbior.2015.09.001"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13475"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.37.23722"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M002759200"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M406512200"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.25.24.11113-11121.2005"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-07-2628"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30674"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.628867"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12447"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.3.1895"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200806072"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100239"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3005580"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0909927107"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100450"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.37961"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa8064"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2011.04544.x"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.111.242859"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00362"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2005.11.003"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39247"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.39938"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2013.09.005"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1005743107"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi980744d"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2005.02.053"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.06.006"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204837"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200318817"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-01-070631"},{"key":"e_1_2_8_37_1","first-page":"3453","article-title":"Neutrophil activation by the tissue factor\/Factor VIIa\/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome","volume":"118","author":"Redecha P.","year":"2008","journal-title":"J. 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