{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:03:10Z","timestamp":1790834590055,"version":"4.1.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T00:00:00Z","timestamp":1585699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,4,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Dysregulated Th17 cell differentiation is associated with autoimmune diseases such as multiple sclerosis, which has no curative treatment. Understanding the molecular mechanisms of regulating Th17 cell differentiation will help find a novel therapeutic target for treating Th17 cell\u2013mediated diseases. In this study, we investigated the cell-intrinsic processes by which RNA-binding protein HuR orchestrates Th17 cell fate decisions by posttranscriptionally regulating transcription factors Irf4 and Runx1 and receptor Il12rb1 expression, in turn promoting Th17 cell and Th1-like Th17 cell differentiation in C57BL\/6J mice. Knockout of HuR altered the transcriptome of Th17 cells characterized by reducing the levels of ROR\u03b3t, IRF4, RUNX1, and T-bet, thereby reducing the number of pathogenic IL-17+IFN-\u03b3+CD4+ T cells in the spleen during experimental autoimmune encephalomyelitis. In keeping with the fact that HuR increased the abundance of adhesion molecule VLA-4 on Th17 cells, knockout of HuR impaired splenic Th17 cell migration to the CNS and abolished the disease. Accordingly, targeting HuR by its inhibitor DHTS inhibited splenic Th17 cell differentiation and reduced experimental autoimmune encephalomyelitis severity. In sum, we uncovered the molecular mechanism of HuR regulating Th17 cell functions, underscoring the therapeutic value of HuR for treatment of autoimmune neuroinflammation.<\/jats:p>","DOI":"10.4049\/jimmunol.1900769","type":"journal-article","created":{"date-parts":[[2020,3,14]],"date-time":"2020-03-14T00:25:47Z","timestamp":1584145547000},"page":"2076-2087","source":"Crossref","is-referenced-by-count":35,"title":["RNA-Binding Protein HuR Promotes Th17 Cell Differentiation and Can Be Targeted to Reduce Autoimmune Neuroinflammation"],"prefix":"10.1093","volume":"204","author":[{"given":"Jing","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurology, Thomas Jefferson University , Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L","family":"Martindale","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Genomics, National Institute on Aging\u2013Intramural Research Program, National Institutes of Health , Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6240-5810","authenticated-orcid":false,"given":"Kotb","family":"Abdelmohsen","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Genomics, National Institute on Aging\u2013Intramural Research Program, National Institutes of Health , Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2298-2212","authenticated-orcid":false,"given":"Gaurav","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Thomas Jefferson University , Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5898-2081","authenticated-orcid":false,"given":"Paolo M","family":"Fortina","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology, Thomas Jefferson University , Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5439-3434","authenticated-orcid":false,"given":"Myriam","family":"Gorospe","sequence":"additional","affiliation":[{"name":"Laboratory of Genetics and Genomics, National Institute on Aging\u2013Intramural Research Program, National Institutes of Health , Baltimore, MD 21224"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0716-2726","authenticated-orcid":false,"given":"Abdolmohamad","family":"Rostami","sequence":"additional","affiliation":[{"name":"Department of Neurology, Thomas Jefferson University , Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7923-3047","authenticated-orcid":false,"given":"Shiguang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Neurology, Thomas Jefferson University , Philadelphia, PA 19107"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,15]]},"reference":[{"key":"2025030417511473700_r1","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/nri3871","article-title":"Immunopathology of multiple sclerosis","volume":"15","author":"Dendrou","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"2025030417511473700_r2","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1084\/jem.20080159","article-title":"IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition","volume":"205","author":"Kroenke","year":"2008","journal-title":"J. Exp. Med."},{"key":"2025030417511473700_r3","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/ni.3389","article-title":"T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis","volume":"17","author":"Martin","year":"2016","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r4","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/ni.2031","article-title":"The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF","volume":"12","author":"El-Behi","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r5","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/nm1715","article-title":"Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells","volume":"14","author":"Stromnes","year":"2008","journal-title":"Nat. Med."},{"key":"2025030417511473700_r6","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2006.07.035","article-title":"The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells","volume":"126","author":"Ivanov","year":"2006","journal-title":"Cell"},{"key":"2025030417511473700_r7","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.immuni.2007.11.016","article-title":"T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma","volume":"28","author":"Yang","year":"2008","journal-title":"Immunity"},{"key":"2025030417511473700_r8","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.immuni.2007.02.009","article-title":"Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation","volume":"26","author":"Laurence","year":"2007","journal-title":"Immunity"},{"key":"2025030417511473700_r9","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1038\/ni1500","article-title":"The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4","volume":"8","author":"Br\u00fcstle","year":"2007","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r10","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1038\/ni.1663","article-title":"Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17-producing T cells [published erratum appears in 2009 Nat. Immunol. 10: 223]","volume":"9","author":"Zhang","year":"2008","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r11","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.immuni.2014.01.002","article-title":"The transcription factors T-bet and Runx are required for the ontogeny of pathogenic interferon-\u03b3-producing T helper 17 cells","volume":"40","author":"Wang","year":"2014","journal-title":"Immunity"},{"key":"2025030417511473700_r12","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1093\/nar\/gkv1066","article-title":"Functional coordination and HuR-mediated regulation of mRNA stability during T cell activation","volume":"44","author":"Blackinton","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"2025030417511473700_r13","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1038\/ni.2884","article-title":"Post-transcriptional coordination of immunological responses by RNA-binding proteins","volume":"15","author":"Kafasla","year":"2014","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r14","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/ni.3115","article-title":"The RNA-binding protein HuR is essential for the B cell antibody response","volume":"16","author":"Diaz-Mu\u00f1oz","year":"2015","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r15","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1073\/pnas.1812536116","article-title":"RNA-binding protein YTHDF3 suppresses interferon-dependent antiviral responses by promoting FOXO3 translation","volume":"116","author":"Zhang","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417511473700_r16","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.immuni.2018.05.008","article-title":"Iron drives T helper cell pathogenicity by promoting RNA-binding protein PCBP1-mediated proinflammatory cytokine production","volume":"49","author":"Wang","year":"2018","journal-title":"Immunity"},{"key":"2025030417511473700_r17","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.immuni.2015.07.021","article-title":"MCPIP1 endoribonuclease activity negatively regulates interleukin-17-mediated signaling and inflammation","volume":"43","author":"Garg","year":"2015","journal-title":"Immunity"},{"key":"2025030417511473700_r18","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1073\/pnas.0306453101","article-title":"Identification of a target RNA motif for RNA-binding protein HuR","volume":"101","author":"L\u00f3pez de Silanes","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417511473700_r19","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1002\/wrna.4","article-title":"Posttranscriptional regulation of cancer traits by HuR","volume":"1","author":"Abdelmohsen","year":"2010","journal-title":"Wiley Interdiscip. Rev. RNA"},{"key":"2025030417511473700_r20","doi-asserted-by":"crossref","first-page":"109","DOI":"10.4049\/immunohorizons.1700017","article-title":"The RNA-binding protein HuR posttranscriptionally regulates IL-2 homeostasis and CD4+ Th2 differentiation","volume":"1","author":"Techasintana","year":"2017","journal-title":"Immunohorizons"},{"key":"2025030417511473700_r21","first-page":"441","article-title":"Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR","volume-title":"J. Immunol.","author":"Stellato","year":"2011"},{"key":"2025030417511473700_r22","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41590-017-0028-4","article-title":"RNA-binding proteins control gene expression and cell fate in the immune system","volume":"19","author":"Turner","year":"2018","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r23","doi-asserted-by":"crossref","first-page":"e1469","DOI":"10.1002\/wrna.1469","article-title":"Complex HuR function in pancreatic cancer cells","volume":"9","author":"Brody","year":"2018","journal-title":"Wiley Interdiscip. Rev. RNA."},{"key":"2025030417511473700_r24","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1172\/JCI38263","article-title":"Essential role of the RNA-binding protein HuR in progenitor cell survival in mice","volume":"119","author":"Ghosh","year":"2009","journal-title":"J. Clin. Invest."},{"key":"2025030417511473700_r25","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0129321","article-title":"Transcriptomic-wide discovery of direct and indirect HuR RNA targets in activated CD4+ T cells","volume":"10","author":"Techasintana","year":"2015","journal-title":"PLoS One"},{"key":"2025030417511473700_r26","first-page":"5441","article-title":"Posttranscriptional gene regulation of IL-17 by the RNA-binding protein HuR is required for initiation of experimental autoimmune encephalomyelitis","volume-title":"J. Immunol.","author":"Chen","year":"2013"},{"key":"2025030417511473700_r27","doi-asserted-by":"crossref","first-page":"17233","DOI":"10.1038\/s41598-017-17371-5","article-title":"Interaction of RNA-binding protein HuR and miR-466i regulates GM-CSF expression","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"2025030417511473700_r28","doi-asserted-by":"crossref","first-page":"14532","DOI":"10.1074\/jbc.M117.782771","article-title":"The RNA-binding protein HuR contributes to neuroinflammation by promoting C-C chemokine receptor 6 (CCR6) expression on Th17 cells","volume":"292","author":"Chen","year":"2017","journal-title":"J. Biol. Chem."},{"key":"2025030417511473700_r29","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jneuroim.2014.05.015","article-title":"The immunomodulator AS101 suppresses production of inflammatory cytokines and ameliorates the pathogenesis of experimental autoimmune encephalomyelitis","volume":"273","author":"Xie","year":"2014","journal-title":"J. Neuroimmunol."},{"key":"2025030417511473700_r30","doi-asserted-by":"crossref","first-page":"9514","DOI":"10.1093\/nar\/gkx623","article-title":"Regulation of HuR structure and function by dihydrotanshinone-I","volume":"45","author":"Lal","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"2025030417511473700_r31","first-page":"3449","article-title":"B cell-intrinsic expression of the HuR RNA-binding protein is required for the T cell-dependent immune response in vivo","volume-title":"J. Immunol.","author":"DeMicco","year":"2015"},{"key":"2025030417511473700_r32","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1084\/jem.20040131","article-title":"CD24 controls expansion and persistence of autoreactive T cells in the central nervous system during experimental autoimmune encephalomyelitis","volume":"200","author":"Bai","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025030417511473700_r33","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1038\/ni1540","article-title":"Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. [Published erratum appears in 2008 Nat. Immunol. 9: 105.]","volume":"8","author":"Fitzgerald","year":"2007","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r34","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/ni.2027","article-title":"ROR\u03b3t drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation","volume":"12","author":"Codarri","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r35","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/nature10075","article-title":"Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand","volume":"472","author":"Solt","year":"2011","journal-title":"Nature"},{"key":"2025030417511473700_r36","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1038\/ni1261","article-title":"A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17","volume":"6","author":"Park","year":"2005","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r37","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1126\/science.1065543","article-title":"Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells","volume":"295","author":"Szabo","year":"2002","journal-title":"Science"},{"key":"2025030417511473700_r38","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1084\/jem.20082584","article-title":"T-bet is essential for encephalitogenicity of both Th1 and Th17 cells","volume":"206","author":"Yang","year":"2009","journal-title":"J. Exp. Med."},{"key":"2025030417511473700_r39","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1038\/ni.2366","article-title":"IL-12 family cytokines: immunological playmakers","volume":"13","author":"Vignali","year":"2012","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r40","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1016\/j.immuni.2019.04.006","article-title":"Fate-mapping of GM-CSF expression identifies a discrete subset of inflammation-driving T helper cells regulated by cytokines IL-23 and IL-1\u03b2","volume":"50","author":"Komuczki","year":"2019","journal-title":"Immunity"},{"key":"2025030417511473700_r41","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/ni794","article-title":"T-bet is a STAT1-induced regulator of IL-12R expression in na\u00efve CD4+ T cells","volume":"3","author":"Afkarian","year":"2002","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r42","doi-asserted-by":"crossref","first-page":"2622","DOI":"10.1056\/NEJMct071462","article-title":"Natalizumab for multiple sclerosis","volume":"356","author":"Ransohoff","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"2025030417511473700_r43","doi-asserted-by":"crossref","first-page":"93","DOI":"10.2119\/molmed.2013.00127","article-title":"Conditional knockout of the RNA-binding protein HuR in CD4+ T cells reveals a gene dosage effect on cytokine production","volume":"20","author":"Gubin","year":"2014","journal-title":"Mol. Med."},{"key":"2025030417511473700_r44","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/ni.1969","article-title":"T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding ROR\u03b3t","volume":"12","author":"Lazarevic","year":"2011","journal-title":"Nat. Immunol."},{"key":"2025030417511473700_r45","doi-asserted-by":"crossref","first-page":"119","DOI":"10.2174\/1573395054065115","article-title":"Interleukin-12: an update on its immunological activities, signaling and regulation of gene expression","volume":"1","author":"Liu","year":"2005","journal-title":"Curr. Immunol. Rev."},{"key":"2025030417511473700_r46","first-page":"5699","article-title":"A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R","volume-title":"J. Immunol.","author":"Parham","year":"2002"},{"key":"2025030417511473700_r47","first-page":"4485","article-title":"Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis","volume-title":"J. Immunol.","author":"Zhang","year":"2003"},{"key":"2025030417511473700_r48","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1084\/jem.20031819","article-title":"Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis","volume":"200","author":"Bettelli","year":"2004","journal-title":"J. Exp. Med."},{"key":"2025030417511473700_r49","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1016\/j.cell.2011.07.033","article-title":"Control of T(H)17\/T(reg) balance by hypoxia-inducible factor 1","volume":"146","author":"Dang","year":"2011","journal-title":"Cell"},{"key":"2025030417511473700_r50","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1128\/MCB.00973-07","article-title":"RNA-binding proteins HuR and PTB promote the translation of hypoxia-inducible factor 1alpha","volume":"28","author":"Galb\u00e1n","year":"2008","journal-title":"Mol. Cell. Biol."},{"key":"2025030417511473700_r51","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0099068","article-title":"Early treatment with anti-VLA-4 mAb can prevent the infiltration and\/or development of pathogenic CD11b+CD4+ T cells in the CNS during progressive EAE","volume":"9","author":"Mindur","year":"2014","journal-title":"PLoS One"},{"key":"2025030417511473700_r52","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1016\/j.cmet.2015.01.004","article-title":"Identification of natural ROR\u03b3 ligands that regulate the development of lymphoid cells","volume":"21","author":"Santori","year":"2015","journal-title":"Cell Metab."},{"key":"2025030417511473700_r53","first-page":"2940","article-title":"Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOS2 gene","volume-title":"J. Immunol.","author":"Fenyk-Melody","year":"1998"},{"key":"2025030417511473700_r54","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1158\/0008-5472.CAN-15-1726","article-title":"HuR small-molecule inhibitor elicits differential effects in adenomatosis polyposis and colorectal carcinogenesis","volume":"77","author":"Lang","year":"2017","journal-title":"Cancer Res."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/204\/8\/2076\/61882739\/ji1900769.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/204\/8\/2076\/61882739\/ji1900769.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T18:40:26Z","timestamp":1741113626000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/204\/8\/2076\/7943955"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4]]},"references-count":54,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2020,4,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1900769","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,4]]},"published":{"date-parts":[[2020,4]]}}}