{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T07:12:30Z","timestamp":1780989150046,"version":"3.54.1"},"reference-count":38,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31871404"],"award-info":[{"award-number":["31871404"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32070768"],"award-info":[{"award-number":["32070768"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31900658"],"award-info":[{"award-number":["31900658"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease with chronic inflammatory demyelination of the CNS. Experimental autoimmune encephalomyelitis (EAE) is an important animal model to study MS, with many pathological phenomena similar to MS. Th17 cells are important regulators of EAE and MS pathogenesis. Most cytokines needed for Th cell development are secreted by APCs, such as dendritic cells (DCs). Consequently, MS could be improved by inhibiting cytokine secretion from DCs. In this study, we reported that chlorzoxazone could ameliorate EAE pathogenesis via inhibiting IL-6 production by DCs. The EAE signs in the chlorzoxazone-treated group of mice were relieved, which was mainly manifested as lower clinical scores, a decrease in the number of immune cells, and a reduction of demyelination in the CNS. Moreover, the proportion of Th17 cells in the spleen and CNS decreased significantly. In vitro experiments showed that chlorzoxazone treatment significantly reduced DC-derived IL-6 production. In the DC\u2013T cell coculture experiment, significantly decreased Th17 differentiation was observed after chlorzoxazone treatment. In addition, mass spectrometric analysis was performed to elucidate the mechanism by which chlorzoxazone affected EAE and DC function. We showed that the effect of chlorzoxazone on inhibiting the secretion of IL-6 by DCs may be mediated via the AMP-activated protein kinase pathway. Overall, our study elucidated the key role of chlorzoxazone in regulating EAE pathogenesis and suggested that it might be used as a new drug for MS patients.<\/jats:p>","DOI":"10.4049\/jimmunol.2100169","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T19:35:12Z","timestamp":1647027312000},"page":"1545-1553","source":"Crossref","is-referenced-by-count":3,"title":["Chlorzoxazone Alleviates Experimental Autoimmune Encephalomyelitis via Inhibiting IL-6 Secretion of Dendritic Cells"],"prefix":"10.1093","volume":"208","author":[{"given":"Jie","family":"Lv","sequence":"first","affiliation":[{"name":"Putuo People\u2019s Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyao","family":"Han","sequence":"additional","affiliation":[{"name":"Putuo People\u2019s Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenglong","family":"Xiang","sequence":"additional","affiliation":[{"name":"Putuo People\u2019s Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Gong","sequence":"additional","affiliation":[{"name":"Putuo People\u2019s Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changjie","family":"Shi","sequence":"additional","affiliation":[{"name":"Putuo People\u2019s Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuhong","family":"Hua","sequence":"additional","affiliation":[{"name":"Putuo People\u2019s Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Putuo People\u2019s Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changsheng","family":"Du","sequence":"additional","affiliation":[{"name":"Putuo People\u2019s Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University , Shanghai,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,1]]},"reference":[{"key":"2025021009002070500_r1","doi-asserted-by":"crossref","first-page":"A5","DOI":"10.1002\/ana.23608","article-title":"Multiple sclerosis drugs: sticker shock","volume":"71","author":"Hauser","year":"2012","journal-title":"Ann. Neurol."},{"key":"2025021009002070500_r2","doi-asserted-by":"crossref","first-page":"41887","DOI":"10.1038\/srep41887","article-title":"Paeoniflorin ameliorates experimental autoimmune encephalomyelitis via inhibition of dendritic cell function and Th17 cell differentiation","volume":"7","author":"Zhang","year":"2017","journal-title":"Sci. Rep."},{"key":"2025021009002070500_r3","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1111\/j.1476-5381.2011.01302.x","article-title":"Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS)","volume":"164","author":"Constantinescu","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"2025021009002070500_r4","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1146\/annurev.immunol.23.021704.115707","article-title":"Immunology of multiple sclerosis","volume":"23","author":"Sospedra","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"2025021009002070500_r5","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1038\/ni1507","article-title":"Multiple sclerosis: a complicated picture of autoimmunity","volume":"8","author":"McFarland","year":"2007","journal-title":"Nat. Immunol."},{"key":"2025021009002070500_r6","doi-asserted-by":"crossref","first-page":"566","DOI":"10.4049\/jimmunol.177.1.566","article-title":"IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis","volume":"177","author":"Komiyama","year":"2006","journal-title":"J. Immunol."},{"key":"2025021009002070500_r7","first-page":"12","article-title":"Th17 cells in MS and experimental autoimmune encephalomyelitis","volume":"16","author":"Hofstetter","year":"2009","journal-title":"Int. MS J."},{"key":"2025021009002070500_r8","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1172\/JCI31720","article-title":"APC-derived cytokines and T cell polarization in autoimmune inflammation","volume":"117","author":"Gutcher","year":"2007","journal-title":"J. Clin. Invest."},{"key":"2025021009002070500_r9","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/nri1246","article-title":"Dendritic-cell control of pathogen-driven T-cell polarization","volume":"3","author":"Kapsenberg","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"2025021009002070500_r10","first-page":"369","article-title":"Centrally acting skeletal-muscle relaxants","volume":"55","author":"Domino","year":"1974","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"2025021009002070500_r11","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s12311-015-0733-1","article-title":"Update on the pharmacotherapy of cerebellar ataxia and nystagmus","volume":"15","author":"Feil","year":"2016","journal-title":"Cerebellum"},{"key":"2025021009002070500_r12","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1212\/WNL.0b013e3182a55f6d","article-title":"Effect of chlorzoxazone in patients with downbeat nystagmus: a pilot trial","volume":"81","author":"Feil","year":"2013","journal-title":"Neurology"},{"key":"2025021009002070500_r13","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41419-020-2357-8","article-title":"Chlorzoxazone, a small molecule drug, augments immunosuppressive capacity of mesenchymal stem cells via modulation of FOXO3 phosphorylation","volume":"11","author":"Deng","year":"2020","journal-title":"Cell Death Dis."},{"key":"2025021009002070500_r14","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/00008571-199906000-00013","article-title":"Chlorzoxazone, a selective probe for phenotyping CYP2E1 in humans","volume":"9","author":"Lucas","year":"1999","journal-title":"Pharmacogenetics"},{"key":"2025021009002070500_r15","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/S0006-8993(02)03730-7","article-title":"Stimulatory effects of chlorzoxazone, a centrally acting muscle relaxant, on large conductance calcium-activated potassium channels in pituitary GH3 cells","volume":"959","author":"Liu","year":"2003","journal-title":"Brain Res."},{"key":"2025021009002070500_r16","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/S0022-3565(24)38803-2","article-title":"Modulation of recombinant small-conductance Ca2+-activated K+ channels by the muscle relaxant chlorzoxazone and structurally related compounds","volume":"296","author":"Cao","year":"2001","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2025021009002070500_r17","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/S0022-3565(24)35351-0","article-title":"Stimulation of Cl\u2212 secretion by chlorzoxazone","volume":"292","author":"Singh","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"2025021009002070500_r18","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1007\/s11481-013-9467-3","article-title":"The immune pathogenesis of multiple sclerosis","volume":"8","author":"Weissert","year":"2013","journal-title":"J. Neuroimmune Pharmacol."},{"key":"2025021009002070500_r19","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1097\/00019052-200206000-00001","article-title":"Pathogenesis of multiple sclerosis: an update on immunology","volume":"15","author":"Hemmer","year":"2002","journal-title":"Curr. Opin. Neurol."},{"key":"2025021009002070500_r20","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/nature11862","article-title":"Metabolism of inflammation limited by AMPK and pseudo-starvation","volume":"493","author":"O\u2019Neill","year":"2013","journal-title":"Nature"},{"key":"2025021009002070500_r21","doi-asserted-by":"crossref","first-page":"e0140452","DOI":"10.1371\/journal.pone.0140452","article-title":"AMPK activation by A-769662 controls IL-6 expression in inflammatory arthritis","volume":"10","author":"Guma","year":"2015","journal-title":"PLoS One"},{"key":"2025021009002070500_r22","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2006.07.035","article-title":"The orphan nuclear receptor ROR\u03b3t directs the differentiation program of proinflammatory IL-17+ T helper cells","volume":"126","author":"Ivanov","year":"2006","journal-title":"Cell"},{"key":"2025021009002070500_r23","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s11481-009-9188-9","article-title":"Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis","volume":"5","author":"El-behi","year":"2010","journal-title":"J. Neuroimmune Pharmacol."},{"key":"2025021009002070500_r24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-3083.2011.02536.x","article-title":"Th17 cell, the new player of neuroinflammatory process in multiple sclerosis","volume":"74","author":"Jadidi-Niaragh","year":"2011","journal-title":"Scand. J. Immunol."},{"key":"2025021009002070500_r25","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cellimm.2005.11.002","article-title":"Therapeutic efficacy of IL-17 neutralization in murine experimental autoimmune encephalomyelitis","volume":"237","author":"Hofstetter","year":"2005","journal-title":"Cell. Immunol."},{"key":"2025021009002070500_r26","doi-asserted-by":"crossref","first-page":"5237","DOI":"10.4049\/jimmunol.1203017","article-title":"IL-17 stimulates differentiation of human anti-inflammatory macrophages and phagocytosis of apoptotic neutrophils in response to IL-10 and glucocorticoids","volume":"190","author":"Zizzo","year":"2013","journal-title":"J. Immunol."},{"key":"2025021009002070500_r27","doi-asserted-by":"crossref","first-page":"7523","DOI":"10.4049\/jimmunol.0803828","article-title":"Natural occurring IL-17 producing T cells regulate the initial phase of neutrophil mediated airway responses","volume":"183","author":"Tanaka","year":"2009","journal-title":"J. Immunol."},{"key":"2025021009002070500_r28","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.biopsych.2010.11.011","article-title":"Chlorzoxazone, an SK-type potassium channel activator used in humans, reduces excessive alcohol intake in rats","volume":"69","author":"Hopf","year":"2011","journal-title":"Biol. Psychiatry"},{"key":"2025021009002070500_r29","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.jpainsymman.2004.05.002","article-title":"Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review","volume":"28","author":"Chou","year":"2004","journal-title":"J. Pain Symptom Manage."},{"key":"2025021009002070500_r30","doi-asserted-by":"crossref","first-page":"106790","DOI":"10.1016\/j.intimp.2020.106790","article-title":"Chlorzoxazone exhibits neuroprotection against Alzheimer\u2019s disease by attenuating neuroinflammation and neurodegeneration in vitro and in vivo","volume":"88","author":"Bai","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"2025021009002070500_r31","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/icb.1997.35","article-title":"The role of dendritic cells in T cell activation","volume":"75","author":"Ni","year":"1997","journal-title":"Immunol. Cell Biol."},{"key":"2025021009002070500_r32","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1046\/j.1365-2567.1999.00860.x","article-title":"Induction of dendritic cell costimulator molecule expression is suppressed by T cells in the absence of antigen-specific signalling: role of cluster formation, CD40 and HLA-class II for dendritic cell activation","volume":"98","author":"McLellan","year":"1999","journal-title":"Immunology"},{"key":"2025021009002070500_r33","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1146\/annurev.iy.09.040191.001415","article-title":"The dendritic cell system and its role in immunogenicity","volume":"9","author":"Steinman","year":"1991","journal-title":"Annu. Rev. Immunol."},{"key":"2025021009002070500_r34","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/cmi.2012.10","article-title":"Regulation of TH17 cell differentiation by innate immune signals","volume":"9","author":"Huang","year":"2012","journal-title":"Cell. Mol. Immunol."},{"key":"2025021009002070500_r35","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/ni.1698","article-title":"The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo","volume":"10","author":"McGeachy","year":"2009","journal-title":"Nat. Immunol."},{"key":"2025021009002070500_r36","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1038\/ni1488","article-title":"IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways","volume":"8","author":"Zhou","year":"2007","journal-title":"Nat. Immunol."},{"key":"2025021009002070500_r37","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1517\/13543784.2012.696609","article-title":"Exploiting the anti-inflammatory effects of AMP-activated protein kinase activation","volume":"21","author":"Salt","year":"2012","journal-title":"Expert Opin. Investig. Drugs"},{"key":"2025021009002070500_r38","doi-asserted-by":"crossref","first-page":"5483","DOI":"10.4049\/jimmunol.179.8.5483","article-title":"Adiponectin enhances IL-6 production in human synovial fibroblast via an AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway","volume":"179","author":"Tang","year":"2007","journal-title":"J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/208\/7\/1545\/61189750\/ji2100169.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/208\/7\/1545\/61189750\/ji2100169.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T09:00:38Z","timestamp":1739178038000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/208\/7\/1545\/7924518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,1]]},"references-count":38,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2022,4,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.2100169","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,4]]},"published":{"date-parts":[[2022,4,1]]}}}