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Our microarray analysis and experimental data indicated a significant expression difference of the long noncoding RNA IL6ST-AS and its anti-sense strand, IL6ST, in \u03b1-synuclein-induced microglia, compared with unstimulated microglia. IL6ST is a key component of the IL6R\/IL6ST complex in the microglial membrane, which recognizes extracellular inflammatory factors, such as IL6. Studies have shown that the binding of IL6 to the IL6R\/IL6ST complex could activate the JAK2-STAT3 pathway and promote an excessive immune response in glia cells. Meanwhile, the phosphorylation and activation of STAT3 could increase the transcription of HIF1A, encoding a hypoxia-inducible factor related to cytotoxic damage. Our results indicated that the overexpression of IL6ST-AS induced by exogenous \u03b1-synuclein could inhibit the expression of IL6ST and the activation of JAK2-STAT3 pathway in HMC3 cells. In addition, a reduction in STAT3 resulted in the transcription inhibition of HIF1A and the acceleration of oxidative stress injury in SH-SY5Y cells co-cultured with \u03b1-synuclein-induced HMC3 cells. Our findings indicate that IL6ST-AS is an important factor that regulates microglia activation and neuronal necrosis in the progression of PD. In the HMC3 and SH-SY5Y cell co-culture system, the overexpression of IL6ST-AS led to microglial dysfunction and neurotoxicology through the IL6ST-AS\/STAT3\/HIF-1\u03b1 axis. Our research revealed the relationships among \u03b1-synuclein, IL6ST, STAT3, and HIF-1\u03b1 in the pathological process of PD and provided a new inflammation hypothesis for the pathogenesis of PD.<\/jats:p>","DOI":"10.3390\/ijms24021436","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T06:18:08Z","timestamp":1673417888000},"page":"1436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["\u03b1-Synuclein Induces Neuroinflammation Injury through the IL6ST-AS\/STAT3\/HIF-1\u03b1 Axis"],"prefix":"10.3390","volume":"24","author":[{"given":"Danyu","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Neurology, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510080, China"},{"name":"Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510080, China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaixun","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5379-675X","authenticated-orcid":false,"given":"Ying","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510080, China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuna","family":"Jing","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510080, China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6527-4967","authenticated-orcid":false,"given":"Enxiang","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China"},{"name":"Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/s41586-018-0104-4","article-title":"Cellular milieu imparts distinct pathological \u03b1-synuclein strains in \u03b1-synucleinopathies","volume":"557","author":"Peng","year":"2018","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1093\/brain\/awaa090","article-title":"Microglial exosomes facilitate \u03b1-synuclein transmission in Parkinson\u2019s disease","volume":"143","author":"Guo","year":"2020","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5089","DOI":"10.1016\/j.cell.2021.09.007","article-title":"Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes","volume":"184","author":"Scheiblich","year":"2021","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.2217\/epi-2019-0222","article-title":"\u03b1-synuclein accumulation in SH-SY5Y cell impairs autophagy in microglia by exosomes overloading 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Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1007\/s12035-014-9070-5","article-title":"Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases","volume":"53","author":"Tang","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1084\/jem.20161810","article-title":"A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis","volume":"214","author":"Schwerd","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Scherger, A.K., Al-Maarri, M., Maurer, H.C., Schick, M., Maurer, S., \u00d6llinger, R., Gonzalez-Menendez, I., Martella, M., Thaler, M., and Pechloff, K. (2019). Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma. JCI Insight, 4.","DOI":"10.1172\/jci.insight.128435"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e141486","DOI":"10.1172\/jci.insight.141486","article-title":"CD109-GP130 interaction drives glioblastoma stem cell plasticity and chemoresistance through STAT3 activity","volume":"6","author":"Filppu","year":"2021","journal-title":"JCI Insight"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.coi.2015.02.008","article-title":"The IL-6\/gp130\/STAT3 signaling axis: Recent advances towards specific inhibition","volume":"34","author":"Garbers","year":"2015","journal-title":"Curr. Opin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1007\/s13238-013-2084-3","article-title":"NF-\u03baB and STAT3 signaling pathways collaboratively link inflammation to cancer","volume":"4","author":"Fan","year":"2013","journal-title":"Protein Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s12974-020-01819-z","article-title":"A primary neural cell culture model to study neuron, astrocyte, and microglia interactions in neuroinflammation","volume":"17","author":"Goshi","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1089\/10430340360535751","article-title":"Stability of mRNA\/cationic lipid lipoplexes in human and rat cerebrospinal fluid: Methods and evidence for nonviral mRNA gene delivery to the central nervous system","volume":"14","author":"Anderson","year":"2003","journal-title":"Hum. Gene Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s12974-017-0939-x","article-title":"Docosahexaenoic acid-containing choline phospholipid modulates LPS-induced neuroinflammation in vivo and in microglia in vitro","volume":"14","author":"Fourrier","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, Q., Zhou, J., Shen, M., Xu, H., Yu, S., Cheng, Q., and Ding, F. (2020). Pyrroloquinoline Quinone Inhibits Rotenone-Induced Microglia Inflammation by Enhancing Autophagy. Molecules, 25.","DOI":"10.3390\/molecules25194359"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3424","DOI":"10.1038\/s41467-021-23832-3","article-title":"Synergistic immunotherapy of glioblastoma by dual targeting of IL-6 and CD40","volume":"12","author":"Yang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1186\/s12974-021-02071-9","article-title":"Activated STAT3 signaling pathway by ligature-induced periodontitis could contribute to neuroinflammation and cognitive impairment in rats","volume":"18","author":"Hu","year":"2021","journal-title":"J. Neuroinflamm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3756","DOI":"10.1111\/jcmm.15056","article-title":"Sanguinarine disrupts the colocalization and interaction of HIF-1\u03b1 with tyrosine and serine phosphorylated-STAT3 in breast cancer","volume":"24","author":"Su","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.2174\/1570159X16666180110130253","article-title":"Understanding the Role of Hypoxia Inducible Factor During Neurodegeneration for New Therapeutics Opportunities","volume":"16","author":"Merelli","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.7150\/thno.29673","article-title":"Interaction between p53 and Ras signaling controls cisplatin resistance via HDAC4- and HIF-1\u03b1-mediated regulation of apoptosis and autophagy","volume":"9","author":"Zhang","year":"2019","journal-title":"Theranostics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1927","DOI":"10.1007\/s10072-019-03905-4","article-title":"Association of HIF1A and Parkinson\u2019s disease in a Han Chinese population demonstrated by molecular inversion probe analysis","volume":"40","author":"Qin","year":"2019","journal-title":"Neurol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1038\/s41419-018-1180-y","article-title":"Brain injury induces HIF-1\u03b1-dependent transcriptional activation of LRRK2 that exacerbates brain damage","volume":"9","author":"Bae","year":"2018","journal-title":"Cell Death. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"180","DOI":"10.14336\/AD.2015.0929","article-title":"Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases","volume":"7","author":"Salminen","year":"2016","journal-title":"Aging Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0299-y","article-title":"Hypoxia signaling in human diseases and therapeutic targets","volume":"51","author":"Lee","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s00726-019-02759-6","article-title":"Up-regulation of HIF-1\u03b1 is associated with neuroprotective effects of agmatine against rotenone-induced toxicity in differentiated SH-SY5Y cells","volume":"52","author":"Ferlazzo","year":"2020","journal-title":"Amino Acids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"41732","DOI":"10.1074\/jbc.M504963200","article-title":"Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system","volume":"280","author":"Siddiq","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5522981","DOI":"10.1155\/2021\/5522981","article-title":"Hypoxia and the Kynurenine Pathway: Implications and Therapeutic Prospects in Alzheimer\u2019s Disease","volume":"2021","author":"Adeyemi","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1436\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:03:07Z","timestamp":1760119387000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/2\/1436"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,11]]},"references-count":29,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24021436"],"URL":"https:\/\/doi.org\/10.3390\/ijms24021436","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,11]]}}}