{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T14:22:33Z","timestamp":1777904553903,"version":"3.51.4"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T00:00:00Z","timestamp":1644192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"The National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31571054, 81430024"],"award-info":[{"award-number":["31571054, 81430024"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Shandong Provincial Key Research and Development Project","award":["2019GSF108224"],"award-info":[{"award-number":["2019GSF108224"]}]},{"name":"the China Postdoctoral Science Foundation","award":["2019M662291"],"award-info":[{"award-number":["2019M662291"]}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2021MC116"],"award-info":[{"award-number":["ZR2021MC116"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Disrupted iron homeostasis in the substantia nigra pars compacta (SNpc) is an important pathological mechanism in Parkinson\u2019s disease (PD). It is unclear what role microglia play in iron metabolism and selective iron deposition in the SNpc of PD brain. In this study, we observed that 6-hydroxydopamine (6-OHDA) induced the expression of divalent metal transporter-1 (DMT1) and iron influx in BV2 microglia cells, which might be associated with the upregulation of iron regulatory protein 1 (IRP1) expression. Moreover, we found that 6-OHDA had no significant effect on the expression of ferroportin 1 (FPN1) and iron efflux in BV2 microglial cells, which might be the combined action of IRP1 upregulation and reduced hepcidin levels. Furthermore, 6-OHDA treatment activated BV2 microglia and enhanced the release of pro-inflammatory cytokines. Interestingly, iron overloading suppressed IRP1 expression, thus downregulating DMT1 and upregulating FPN1 levels in these microglial cells. On the contrary, iron deficiency activated IRP1, leading to increased expression of DMT1 and decreased expression of FPN1\u2014which indicates that activated IRP1 induces iron overloading in 6-OHDA-treated microglia, but not iron overloading modulates the expression of IRP1. Taken together, our data suggest that 6-OHDA can regulate the expression of DMT1 and FPN1 by activating IRP1 and inhibiting hepcidin release, thus leading to abnormal iron sequestration in microglia. In addition, 6-OHDA can activate microglia, which leads to increased release of pro-inflammatory factors that can further induce genome damage in dopaminergic neurons.<\/jats:p>","DOI":"10.3390\/biom12020266","type":"journal-article","created":{"date-parts":[[2022,2,7]],"date-time":"2022-02-07T08:38:48Z","timestamp":1644223128000},"page":"266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["6-Hydroxydopamine Induces Abnormal Iron Sequestration in BV2 Microglia by Activating Iron Regulatory Protein 1 and Inhibiting Hepcidin Release"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1297-9477","authenticated-orcid":false,"given":"Manman","family":"Xu","sequence":"first","affiliation":[{"name":"School of Basic Medicine, Qingdao University, Qingdao 266071, China"},{"name":"Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao 266071, China"},{"name":"Medical Service Section, The Affiliated Hospital of Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yinghui","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Qingdao University, Qingdao 266071, China"},{"name":"Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dapeng","family":"Meng","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Qingdao University, Qingdao 266071, China"},{"name":"Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1280-9248","authenticated-orcid":false,"given":"Danyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Qingdao University, Qingdao 266071, China"},{"name":"Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingjing","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Qingdao University, Qingdao 266071, China"},{"name":"Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junxia","family":"Xie","sequence":"additional","affiliation":[{"name":"Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Qingdao University, Qingdao 266071, China"},{"name":"Institute of Brain Science and Disease, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao 266071, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.pneurobio.2008.05.003","article-title":"Progress in Parkinson\u2019s disease-where do we stand?","volume":"85","author":"Toulouse","year":"2008","journal-title":"Prog. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/mds.27888","article-title":"Blood biomarkers with Parkinson\u2019s disease clusters and prognosis: The oxford discovery cohort","volume":"35","author":"Lawton","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"612","DOI":"10.3389\/fnins.2018.00612","article-title":"Parkinson\u2019s Disease: Biomarkers, Treatment, and Risk Factors","volume":"12","author":"Emamzadeh","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1016\/S0891-5849(02)00804-3","article-title":"The relationship between oxidative\/nitrative stress and pathological inclusions in Alzheimer\u2019s and Parkinson\u2019s diseases","volume":"32","author":"Giasson","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0303-8467(98)00009-2","article-title":"Genetic and environmental risk factors in Parkinson\u2019s disease","volume":"100","author":"Veldman","year":"1998","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S1353-8020(01)00055-4","article-title":"Evidence for environmental causation of Parkinson\u2019s disease","volume":"8","author":"Calne","year":"2002","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1021\/acschemneuro.8b00390","article-title":"Iron Dysregulation in Parkinson\u2019s Disease: Focused on the Autophagy-Lysosome Pathway","volume":"10","author":"Chen","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1007\/s12264-020-00585-5","article-title":"Axonal Iron Transport might Contribute to Iron Deposition in Parkinson\u2019s Disease","volume":"37","author":"Chen","year":"2021","journal-title":"Neurosci. Bull."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2766","DOI":"10.1111\/j.1460-9568.2007.05515.x","article-title":"Ferroportin1 and hephaestin are involved in the nigral iron accumulation of 6-OHDA-lesioned rats","volume":"25","author":"Wang","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/cr.2010.20","article-title":"Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE\/IRP dependent","volume":"20","author":"Jiang","year":"2010","journal-title":"Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.freeradbiomed.2009.11.004","article-title":"Ferroportin 1 but not hephaestin contributes to iron accumulation in a cell model of Parkinson\u2019s disease","volume":"48","author":"Song","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/S0014-4886(03)00123-7","article-title":"Dopamine release rather than content in the caudate putamen is associated with behavioral changes in the iron rat model of Parkinson\u2019s disease","volume":"182","author":"Junxia","year":"2003","journal-title":"Exp. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1089\/ars.2014.5874","article-title":"Iron in neurodegenerative disorders of protein misfolding: A case of prion disorders and Parkinson\u2019s disease","volume":"21","author":"Singh","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1080\/15548627.2017.1371393","article-title":"Phosphoproteome-based kinase activity profiling reveals the critical role of MAP2K2 and PLK1 in neuronal autophagy","volume":"13","author":"Chen","year":"2017","journal-title":"Autophagy"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.freeradbiomed.2018.07.020","article-title":"DMT1 and iron transport","volume":"133","author":"Yanatori","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1006\/bcmd.1998.0186","article-title":"The human Nramp2 gene: Characterization of the gene structure, alternative splicing, promoter region and polymorphisms","volume":"24","author":"Lee","year":"1998","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1146\/annurev.nutr.20.1.627","article-title":"Iron regulatory proteins and the molecular control of mammalian iron metabolism","volume":"20","author":"Eisenstein","year":"2000","journal-title":"Annu. Rev. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.cmet.2007.10.006","article-title":"Iron regulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum","volume":"7","author":"Galy","year":"2008","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.cmet.2005.02.005","article-title":"Cellular iron: Ferroportin is the only way out","volume":"1","author":"Ganz","year":"2005","journal-title":"Cell Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S1097-2765(00)80282-8","article-title":"IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F","volume":"2","author":"Muckenthaler","year":"1998","journal-title":"Mol. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2090","DOI":"10.1126\/science.1104742","article-title":"Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization","volume":"306","author":"Nemeth","year":"2004","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1182\/blood-2011-01-330241","article-title":"Hepcidin regulates ferroportin expression and intracellular iron homeostasis of erythroblasts","volume":"118","author":"Zhang","year":"2011","journal-title":"Blood"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1002\/mds.21020","article-title":"Iron metabolism in Parkinsonian syndromes","volume":"21","author":"Berg","year":"2006","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.neulet.2009.05.033","article-title":"Meloxicam reduces lipopolysaccharide-induced degeneration of dopaminergic neurons in the rat substantia nigra pars compacta","volume":"460","author":"Sui","year":"2009","journal-title":"Neurosci. Lett."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1212\/WNL.38.8.1285","article-title":"Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson\u2019s and Alzheimer\u2019s disease brains","volume":"38","author":"McGeer","year":"1988","journal-title":"Neurology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s10534-013-9647-x","article-title":"6-Hydroxydopamine promotes iron traffic in primary cultured astrocytes","volume":"26","author":"Zhang","year":"2013","journal-title":"Biometals Int. J. Role Met. Ions Biol. Biochem. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2967","DOI":"10.1016\/j.bbamcr.2014.09.010","article-title":"Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor inhibit ferrous iron influx via divalent metal transporter 1 and iron regulatory protein 1 regulation in ventral mesencephalic neurons","volume":"1843","author":"Zhang","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7600","DOI":"10.1002\/jcp.27522","article-title":"Hepcidin and iron regulatory proteins coordinately regulate ferroportin 1 expression in the brain of mice","volume":"234","author":"Wang","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Nemeth, E., and Ganz, T. (2021). Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126493"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1007\/s12011-011-8967-3","article-title":"Hepcidin treatment modulates the expression of divalent metal transporter-1, ceruloplasmin, and ferroportin-1 in the rat cerebral cortex and hippocampus","volume":"143","author":"Li","year":"2011","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7853","DOI":"10.1074\/jbc.RA118.001949","article-title":"Inflammation-induced iron transport and metabolism by brain microglia","volume":"293","author":"McCarthy","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1002\/glia.22350","article-title":"Microglia and neurodegeneration: The role of systemic inflammation","volume":"61","author":"Cunningham","year":"2013","journal-title":"Glia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/s41593-018-0242-x","article-title":"Microglia in neurodegeneration","volume":"10","author":"Hickman","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/mds.21751","article-title":"Glial reactions in Parkinson\u2019s disease","volume":"23","author":"McGeer","year":"2008","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrneurol.2014.207","article-title":"Microglial and macrophage polarization\u2014New prospects for brain repair","volume":"11","author":"Hu","year":"2015","journal-title":"Nat. Rev. Neurol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/2\/266\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:15:16Z","timestamp":1760134516000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/12\/2\/266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,7]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["biom12020266"],"URL":"https:\/\/doi.org\/10.3390\/biom12020266","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,7]]}}}