{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:43:11Z","timestamp":1790905391706,"version":"4.1.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T00:00:00Z","timestamp":1681948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Vagus nerve stimulation (VNS) has a protective effect on neurological recovery in ischaemic stroke. However, its underlying mechanism remains to be clarified. Ubiquitin-specific protease 10 (USP10), a member of the ubiquitin-specific protease family, has been shown to inhibit the activation of the NF-\u03baB signalling pathway. Therefore, this study investigated whether USP10 plays a key role in the protective effect of VNS against ischemic stroke and explore its mechanism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Ischaemic stroke model was constructed by transient middle cerebral artery occlusion (tMCAO) in mice. VNS was performed at\u00a030 min,\u00a024hr, and 48hr after the establishment of tMCAO model. USP10 expression induced by VNS after tMCAO was measured. LV-shUSP10 was used to establish the model with low expression of USP10 by stereotaxic injection technique. The effects of VNS with or without USP10 silencing on neurological deficits, cerebral infarct volume, NF-\u03baB pathway activation, glial cell activation, and release of pro-inflammation cytokines were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>VNS enhanced the expression of USP10 following tMCAO. VNS ameliorated neurological deficits and reduced cerebral infarct volume, but this effect was inhibited by silencing of USP10. Activation of the NF-\u03baB pathway and the expression of inflammatory cytokines induced by tMCAO were suppressed by VNS. Moreover, VNS promoted the pro-to-anti-inflammatory response of microglia and inhibited activation of astrocytes, while silencing of USP10 prevented the neuroprotective and anti-neuroinflammatory effects of VNS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>USP10 is a potential mediator for VNS to alleviate neurological deficits, neuroinflammation, and glial cell activation in ischaemic stroke by inhibiting NF-\u03baB signalling pathway.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1130697","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T21:08:55Z","timestamp":1682024935000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":24,"title":["USP10 is a potential mediator for vagus nerve stimulation to alleviate neuroinflammation in ischaemic stroke by inhibiting NF-\u03baB signalling pathway"],"prefix":"10.3389","volume":"14","author":[{"given":"Chenchen","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changqing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,4,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/s1474-4422(21)00252-0","article-title":"Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the global burden of disease study 2019","volume":"20","author":"Feigin","year":"2021","journal-title":"Lancet Neurol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1013311","article-title":"Microglia autophagy in ischemic stroke: a double-edged sword","volume":"13","author":"Peng","year":"2022","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.121.038351","article-title":"NF-\u03baB signaling-mediated activation of WNK-SPAK-NKCC1 cascade in worsened stroke outcomes of ang II-hypertensive mice","volume":"53","author":"Bhuiyan","year":"2022","journal-title":"Stroke"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.197","article-title":"HSCARG downregulates NF-\u03baB signaling by interacting with USP7 and inhibiting NEMO ubiquitination","volume":"5","author":"Li","year":"2014","journal-title":"Cell Death Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.247","article-title":"USP10 inhibits genotoxic NF-\u03baB activation by MCPIP1-facilitated deubiquitination of NEMO","volume":"32","author":"Niu","year":"2013","journal-title":"EMBO J"},{"key":"B6","doi-asserted-by":"publisher","first-page":"101059","DOI":"10.1016\/j.redox.2018.11.017","article-title":"NRF2 and NF-\u03baB interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches","volume":"21","author":"Sivandzade","year":"2019","journal-title":"Redox Biol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.120.316659","article-title":"Targeting myeloid-specific integrin \u03b19\u03b21 improves short- and long-term stroke outcomes in murine models with preexisting comorbidities by limiting thrombosis and inflammation","volume":"126","author":"Dhanesha","year":"2020","journal-title":"Circ Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/circheartfailure.122.009288","article-title":"Transcutaneous vagus nerve stimulation ameliorates the phenotype of heart failure with preserved ejection fraction through its anti-inflammatory effects","volume":"15","author":"Elkholey","year":"2022","journal-title":"Circ Heart Fail"},{"key":"B9","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1126\/science.1209985","article-title":"Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit","volume":"334","author":"Rosas-Ballina","year":"2011","journal-title":"Science"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20102574","article-title":"Modern concepts in regenerative therapy for ischemic stroke: from stem cells for promoting angiogenesis to 3D-bioprinted scaffolds customized via carotid shear stress analysis","volume":"20","author":"Benedek","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(21)00300-8","article-title":"Neuromodulation in epilepsy: state-of-the-art approved therapies","volume":"20","author":"Ryvlin","year":"2021","journal-title":"Lancet Neurol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.neubiorev.2021.04.018","article-title":"Vagus nerve stimulation in brain diseases: therapeutic applications and biological mechanisms","volume":"127","author":"Wang","year":"2021","journal-title":"Neurosci Biobehav Rev"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2015.11.008","article-title":"Transcutaneous cervical vagus nerve stimulation ameliorates acute ischemic injury in rats","volume":"9","author":"Ay","year":"2016","journal-title":"Brain Stimul"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-016-2121-8","article-title":"L-PGDS mediates vagus nerve stimulation-induced neuroprotection in a rat model of ischemic stroke by suppressing the apoptotic response","volume":"42","author":"Zhang","year":"2017","journal-title":"Neurochem Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/s41420-022-00852-6","article-title":"Vagus nerve stimulation alleviated cerebral ischemia and reperfusion injury in rats by inhibiting pyroptosis via \u03b17 nicotinic acetylcholine receptor","volume":"8","author":"Tang","year":"2022","journal-title":"Cell Death Discov"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2021.09.004","article-title":"Vagus nerve stimulation mediates microglia M1\/2 polarization via inhibition of TLR4 pathway after ischemic stroke","volume":"577","author":"Zhang","year":"2021","journal-title":"Biochem Biophys Res Commun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2018.11.006","article-title":"USP10 is a driver of ubiquitinated protein aggregation and aggresome formation to inhibit apoptosis","volume":"9","author":"Takahashi","year":"2018","journal-title":"iScience"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.08.037","article-title":"Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13","volume":"147","author":"Liu","year":"2011","journal-title":"Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/hep.30062","article-title":"Ubiquitin-specific peptidase 10 (USP10) inhibits hepatic steatosis, insulin resistance, and inflammation through Sirt6","volume":"68","author":"Luo","year":"2018","journal-title":"Hepatology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.06.042","article-title":"USP10 protects against cerebral ischemia injury by suppressing inflammation and apoptosis through the inhibition of TAK1 signaling","volume":"516","author":"Wang","year":"2019","journal-title":"Biochem Biophys Res Commun"},{"key":"B21","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1161\/01.str.20.1.84","article-title":"Reversible middle cerebral artery occlusion without craniectomy in rats","volume":"20","author":"Longa","year":"1989","journal-title":"Stroke"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.07.038","article-title":"Electroacupuncture modulates stromal cell-derived factor-1\u03b1 expression and mobilization of bone marrow endothelial progenitor cells in focal cerebral ischemia\/reperfusion model rats","volume":"1648","author":"Xie","year":"2016","journal-title":"Brain Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.brainresbull.2018.02.011","article-title":"Growth differentiation factor 11 improves neurobehavioral recovery and stimulates angiogenesis in rats subjected to cerebral ischemia\/reperfusion","volume":"139","author":"Ma","year":"2018","journal-title":"Brain Res Bull"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.08.002","article-title":"Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke","volume":"60","author":"Khodaparast","year":"2013","journal-title":"Neurobiol Dis"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/3858314","article-title":"Molecular mechanism of epimedium extract against ischemic stroke based on network pharmacology and experimental validation","volume":"2022","author":"Xu","year":"2022","journal-title":"Oxid Med Cell Longev"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2020.1802089","article-title":"BNIP3L\/NIX degradation leads to mitophagy deficiency in ischemic brains","volume":"17","author":"Wu","year":"2021","journal-title":"Autophagy"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.107.500801","article-title":"Insulin growth factor-1 gene transfer enhances neurovascular remodeling and improves long-term stroke outcome in mice","volume":"39","author":"Zhu","year":"2008","journal-title":"Stroke"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/8131391","article-title":"Effects of long-term vagus nerve electrical stimulation therapy on acute cerebral infarction and neurological function recovery in post MCAO mice","volume":"2022","author":"Du","year":"2022","journal-title":"Oxid Med Cell Longev"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1161\/hs1101.098367","article-title":"Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats","volume":"32","author":"Chen","year":"2001","journal-title":"Stroke"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2013.10.028","article-title":"Assessment of behavioral flexibility after middle cerebral artery occlusion in mice","volume":"258","author":"Linden","year":"2014","journal-title":"Behav Brain Res"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.940166","article-title":"Molecular mechanism of epimedium in the treatment of vascular dementia based on network pharmacology and molecular docking","volume":"14","author":"Xie","year":"2022","journal-title":"Front Aging Neurosci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.4103\/2347-8659.139719","article-title":"A novel method for evaluating microglial activation using ionized calcium-binding adaptor protein-1 staining: cell body to cell size ratio","volume":"1","author":"Hovens","year":"2014","journal-title":"Neuroimmunol Neuroinflamm"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3791\/57648","article-title":"Quantifying microglia morphology from photomicrographs of immunohistochemistry prepared tissue using ImageJ","volume":"5","author":"Young","year":"2018","journal-title":"J Vis Exp"},{"key":"B34","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1083\/jcb.200611141","article-title":"Error bars in experimental biology","volume":"177","author":"Cumming","year":"2007","journal-title":"J Cell Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.09.014","article-title":"Microglia: immune and non-immune functions","volume":"54","author":"Borst","year":"2021","journal-title":"IMMUNITY"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-00783-4","article-title":"Reactive astrocyte nomenclature, definitions, and future directions","volume":"24","author":"Escartin","year":"2021","journal-title":"Nat Neurosci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.2147\/ndt.S196665","article-title":"Durability of symptomatic responses obtained with adjunctive vagus nerve stimulation in treatment-resistant depression","volume":"15","author":"Kumar","year":"2019","journal-title":"Neuropsychiatr Dis Treat"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2015.3972","article-title":"Vagus nerve stimulation delivered with motor training enhances recovery of function after traumatic brain injury","volume":"33","author":"Pruitt","year":"2016","journal-title":"J Neurotrauma"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fnhum.2022.866434","article-title":"Vagus nerve stimulation as a potential therapy in early alzheimer's disease: a review","volume":"16","author":"Vargas-Caballero","year":"2022","journal-title":"Front Hum Neurosci"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1161\/strokeaha.117.019202","article-title":"Vagus nerve stimulation enhances stable plasticity and generalization of stroke recovery","volume":"49","author":"Meyers","year":"2018","journal-title":"Stroke"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)00475-x","article-title":"Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial","volume":"397","author":"Dawson","year":"2021","journal-title":"Lancet"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-03-493718","article-title":"HTLV-1 tax oncoprotein stimulates ROS production and apoptosis in T cells by interacting with USP10","volume":"122","author":"Takahashi","year":"2013","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.00763-12","article-title":"Stress granules inhibit apoptosis by reducing reactive oxygen species production","volume":"33","author":"Takahashi","year":"2013","journal-title":"Mol Cell Biol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nrneurol.2014.207","article-title":"Microglial and macrophage polarization\u2013new prospects for brain repair","volume":"11","author":"Hu","year":"2015","journal-title":"Nat Rev Neurol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jstrokecerebrovasdis.2022.106390","article-title":"Effect of combined vagus nerve stimulation on recovery of upper extremity function in patients with stroke: a systematic review and meta-analysis","volume":"31","author":"Liu","year":"2022","journal-title":"J Stroke Cerebrovasc Dis"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.brs.2018.01.034","article-title":"Non-invasive vagus nerve stimulation reduces blood-brain barrier disruption in a rat model of ischemic stroke","volume":"11","author":"Yang","year":"2018","journal-title":"Brain Stimul"},{"key":"B47","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s12974-019-1516-2","article-title":"Neuroinflammation: friend and foe for ischemic stroke","volume":"16","author":"Jayaraj","year":"2019","journal-title":"J Neuroinflamm"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4103\/1673-5374.350698","article-title":"Vagus nerve stimulation is a potential treatment for ischemic stroke","volume":"18","author":"Liu","year":"2023","journal-title":"Neural Regener Res"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fnbeh.2022.811419","article-title":"Transcutaneous auricular vagus nerve stimulation promotes white matter repair and improves dysphagia symptoms in cerebral ischemia model rats","volume":"16","author":"Long","year":"2022","journal-title":"Front Behav Neurosci"},{"key":"B50","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.molcel.2010.09.010","article-title":"ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress","volume":"40","author":"Wu","year":"2010","journal-title":"Mol Cell"},{"key":"B51","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.immuni.2016.12.009","article-title":"Vagal regulation of group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution","volume":"46","author":"Dalli","year":"2017","journal-title":"Immunity"},{"key":"B52","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/s1474-4422(15)70016-5","article-title":"Neuroinflammation in alzheimer's disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol"},{"key":"B53","doi-asserted-by":"publisher","first-page":"6176","DOI":"10.1038\/ncomms7176","article-title":"Microglia constitute a barrier that prevents neurotoxic protofibrillar A\u03b242 hotspots around plaques","volume":"6","author":"Condello","year":"2015","journal-title":"Nat Commun"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.10.012","article-title":"Sphingosine-1-phosphate, a novel TREM2 ligand, promotes microglial phagocytosis to protect against ischemic brain injury","volume":"12","author":"Xue","year":"2022","journal-title":"Acta Pharm Sin B"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1007\/s12031-018-1227-7","article-title":"Non-invasive vagus nerve stimulation protects against cerebral Ischemia\/Reperfusion injury and promotes microglial M2 polarization via interleukin-17A inhibition","volume":"67","author":"Zhao","year":"2019","journal-title":"J Mol Neurosci"},{"key":"B56","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12950-016-0140-5","article-title":"Electric stimulation of the vagus nerve reduced mouse neuroinflammation induced by lipopolysaccharide","volume":"13","author":"Meneses","year":"2016","journal-title":"J Inflammation (Lond)"},{"key":"B57","doi-asserted-by":"publisher","first-page":"R88","DOI":"10.1186\/cc9019","article-title":"The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction","volume":"14","author":"Terrando","year":"2010","journal-title":"Crit Care"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104769","article-title":"Stress-induced blood brain barrier disruption: molecular mechanisms and signaling pathways","volume":"157","author":"Welcome","year":"2020","journal-title":"Pharmacol Res"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00041.2013","article-title":"Astrocyte reactivity and reactive astrogliosis: costs and benefits","volume":"94","author":"Pekny","year":"2014","journal-title":"Physiol Rev"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24253","article-title":"Ezrin deficiency triggers glial fibrillary acidic protein upregulation and a distinct reactive astrocyte phenotype","volume":"70","author":"Schacke","year":"2022","journal-title":"GLIA"},{"key":"B61","doi-asserted-by":"publisher","first-page":"6943","DOI":"10.1038\/s41467-021-27248-x","article-title":"Stroke subtype-dependent synapse elimination by reactive gliosis in mice","volume":"12","author":"Shi","year":"2021","journal-title":"Nat Commun"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/8163789","article-title":"PPAR-\u03b3 mediates Ta-VNS-Induced angiogenesis and subsequent functional recovery after experimental stroke in rats","volume":"2020","author":"Li","year":"2020","journal-title":"BioMed Res Int"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1130697\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T21:08:59Z","timestamp":1682024939000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1130697\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,20]]},"references-count":62,"alternative-id":["10.3389\/fimmu.2023.1130697"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1130697","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,20]]},"article-number":"1130697"}}