{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:35:17Z","timestamp":1791318917885,"version":"4.3.1"},"reference-count":31,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:00:00Z","timestamp":1703203200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004844","name":"National Cheng Kung University Hospital of Taiwan","doi-asserted-by":"publisher","award":["NCKUH-11104006"],"award-info":[{"award-number":["NCKUH-11104006"]}],"id":[{"id":"10.13039\/501100004844","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004844","name":"National Cheng Kung University Hospital of Taiwan","doi-asserted-by":"publisher","award":["TNHPA11010"],"award-info":[{"award-number":["TNHPA11010"]}],"id":[{"id":"10.13039\/501100004844","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tainan Hospital, Ministry of Health and Welfare of Taiwan","award":["NCKUH-11104006"],"award-info":[{"award-number":["NCKUH-11104006"]}]},{"name":"Tainan Hospital, Ministry of Health and Welfare of Taiwan","award":["TNHPA11010"],"award-info":[{"award-number":["TNHPA11010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Preeclampsia (PE) remains one of the leading causes of maternal and perinatal morbidity and mortality. However, the exact pathophysiology of PE is still unclear. The recent widely accepted notion that successful pregnancy relies on maternal immunological adaptation is of utmost importance. Moreover, salt-inducible kinase 3 (SIK3) is an AMP-activated protein kinase-related kinase, and it has reported a novel regulator of energy and inflammation, and its expression related with some diseases. To explore whether SIK3 expression correlated with PE, we analyzed SIK3 gene expression and its association with PE through GEO datasets. We identified that SIK3 was significantly downregulated in PE across four datasets (p &lt; 0.05), suggesting that SIK3 participated in the pathogenesis of PE. We initially demonstrated the significant downregulation of SIK3 in trophoblast cells of PE. SIK3 downregulation was positively correlated with the increased number of CD204(+) cells in in vivo and in vitro experiments. The increased number of CD204(+) cells could inhibit the migration and invasion of trophoblast cells. We then clarified the potential mechanism of PE with SIK3 downregulation: M2 skewing was triggered by trophoblast cells derived via the CCL24\/CCR3 axis, leading to an increase in CD204(+) cells, a decrease in phagocytosis, and the production of IL-10 at the maternal\u2013fetal interface of the placenta with PE. IL-10 further contributed to a reduction in the migration and invasion of trophoblast cells. It also established a feedback loop wherein trophoblast cells increased CCL24 production to maintain M2 dominance in the placental environments of PE.<\/jats:p>","DOI":"10.3390\/ijms25010222","type":"journal-article","created":{"date-parts":[[2023,12,24]],"date-time":"2023-12-24T20:44:15Z","timestamp":1703450655000},"page":"222","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Downregulation of Salt-Inducible Kinase 3 Enhances CCL24 Activation in the Placental Environment with Preeclampsia"],"prefix":"10.3390","volume":"25","author":[{"given":"Hsing-Fen","family":"Tsai","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Fen","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ling","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8168-6125","authenticated-orcid":false,"given":"Pei-Ying","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lan-Yin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Han","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Hsuan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tainan Hospital, Ministry of Health and Welfare of Taiwan, Tainan 70101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Ni","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2698-4971","authenticated-orcid":false,"given":"Keng-Fu","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704302, Taiwan"},{"name":"Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1146\/annurev-pathol-121808-102149","article-title":"Pathogenesis of preeclampsia","volume":"5","author":"Young","year":"2010","journal-title":"Annu. Rev. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ogc.2010.02.013","article-title":"Abnormal placentation, angiogenic factors, and the pathogenesis of preeclampsia","volume":"37","author":"Silasi","year":"2010","journal-title":"Obstet. Gynecol. Clin. N. Am."},{"key":"ref_3","unstructured":"National Collaborating Centre for Women\u2019s and Children\u2019s Health (2010). NICE Clinical Guidelines, No. 107. Hypertension in Pregnancy: The Management of Hypertensive Disorders during Pregnancy, RCOG Press."},{"key":"ref_4","unstructured":"WHO Guidelines Approved by the Guidelines Review Committee (2011). WHO Recommendations for Prevention and Treatment of Pre-Eclampsia and Eclampsia, World Health Organization."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.humimm.2021.01.004","article-title":"Review of the immune mechanisms of preeclampsia and the potential of immune modulating therapy","volume":"82","author":"Collier","year":"2021","journal-title":"Hum. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1038\/s41581-019-0119-6","article-title":"Pre-eclampsia: Pathogenesis, novel diagnostics and therapies","volume":"15","author":"Phipps","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1161\/CIRCRESAHA.118.313276","article-title":"Preeclampsia: Pathophysiology, Challenges, and Perspectives","volume":"124","author":"Rana","year":"2019","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1042\/BCJ20160646","article-title":"Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages","volume":"474","author":"Darling","year":"2017","journal-title":"Biochem. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"6025","DOI":"10.7150\/jca.34886","article-title":"Downregulated Salt-inducible Kinase 3 Expression Promotes Chemoresistance in Serous Ovarian Cancer via the ATP-binding Cassette Protein ABCG2","volume":"10","author":"Liang","year":"2019","journal-title":"J. Cancer"},{"key":"ref_10","first-page":"2505","article-title":"Expression of inflammatory cytokines in placentas from women with preeclampsia","volume":"86","author":"Benyo","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1530\/REP-09-0007","article-title":"Altered decidual leucocyte populations in the placental bed in pre-eclampsia and foetal growth restriction: A comparison with late normal pregnancy","volume":"138","author":"Williams","year":"2009","journal-title":"Reproduction"},{"key":"ref_12","first-page":"171","article-title":"Pregnancy immunology: Decidual immune cells","volume":"26","author":"Sanguansermsri","year":"2008","journal-title":"Asian Pac. J. Allergy Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.bpobgyn.2019.05.009","article-title":"Decidual immune cells: Guardians of human pregnancies","volume":"60","author":"Solano","year":"2019","journal-title":"Best. Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.3389\/fimmu.2018.02087","article-title":"Decidual-Placental Immune Landscape during Syngeneic Murine Pregnancy","volume":"9","author":"Li","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s00441-015-2315-4","article-title":"To serve and to protect: The role of decidual innate immune cells on human pregnancy","volume":"363","author":"Zhang","year":"2016","journal-title":"Cell Tissue Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"655655","DOI":"10.3389\/fimmu.2021.655655","article-title":"Dysfunction of Decidual Macrophages Is a Potential Risk Factor in the Occurrence of Preeclampsia","volume":"12","author":"Rong","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s10565-022-09767-5","article-title":"CCL24\/CCR3 axis plays a central role in angiotensin II-induced heart failure by stimulating M2 macrophage polarization and fibroblast activation","volume":"39","author":"Wang","year":"2023","journal-title":"Cell Biol. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1189\/jlb.1A0815-351R","article-title":"Decidual macrophages: Key regulators of vascular remodeling in human pregnancy","volume":"100","author":"Lash","year":"2016","journal-title":"J. Leukoc. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"792","DOI":"10.3389\/fimmu.2019.00792","article-title":"Macrophage Polarization in Physiological and Pathological Pregnancy","volume":"10","author":"Yao","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41581-022-00670-0","article-title":"The role of immune cells and mediators in preeclampsia","volume":"19","author":"Deer","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.ajpath.2010.10.011","article-title":"Differential distribution and phenotype of decidual macrophages in preeclamptic versus control pregnancies","volume":"178","author":"Schonkeren","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"298","DOI":"10.3389\/fimmu.2014.00298","article-title":"Monocytes and macrophages in pregnancy and pre-eclampsia","volume":"5","author":"Faas","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e15080","DOI":"10.1097\/MD.0000000000015080","article-title":"Immune imbalance is associated with the development of preeclampsia","volume":"98","author":"Ma","year":"2019","journal-title":"Medicine"},{"key":"ref_24","first-page":"1028","article-title":"Trophoblasts-derived chemokine CCL24 promotes the proliferation, growth and apoptosis of decidual stromal cells in human early pregnancy","volume":"6","author":"Li","year":"2013","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1093\/humrep\/det060","article-title":"Control of extravillous trophoblast function by the eotaxins CCL11, CCL24 and CCL26","volume":"28","author":"Chau","year":"2013","journal-title":"Hum. Reprod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1530\/REP-15-0119","article-title":"Chemokine CCL24 promotes the growth and invasiveness of trophoblasts through ERK1\/2 and PI3K signaling pathways in human early pregnancy","volume":"150","author":"Li","year":"2015","journal-title":"Reproduction"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1365-2249.2010.04248.x","article-title":"Increased expression of chemokine receptor CCR3 and its ligands in ulcerative colitis: The role of colonic epithelial cells in in vitro studies","volume":"162","author":"Manousou","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e20190418","DOI":"10.1084\/jem.20190418","article-title":"Biology and therapeutic potential of interleukin-10","volume":"217","author":"Saraiva","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1161\/HYPERTENSIONAHA.120.15870","article-title":"Preeclamptic Women Have Decreased Circulating IL-10 (Interleukin-10) Values at the Time of Preeclampsia Diagnosis: Systematic Review and Meta-Analysis","volume":"76","author":"Nath","year":"2020","journal-title":"Hypertension"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s11906-018-0833-7","article-title":"The Role of Interleukin-10 in the Pathophysiology of Preeclampsia","volume":"20","author":"Cubro","year":"2018","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3491","DOI":"10.4049\/jimmunol.163.6.3491","article-title":"A deficiency of the placental IL-10 in preeclampsia","volume":"163","author":"Hennessy","year":"1999","journal-title":"J. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/222\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:40:41Z","timestamp":1760132441000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/222"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,22]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25010222"],"URL":"https:\/\/doi.org\/10.3390\/ijms25010222","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,22]]}}}