{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:25:46Z","timestamp":1792686346248,"version":"4.5.0"},"reference-count":62,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81471598"],"award-info":[{"award-number":["81471598"]}],"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":["81671593"],"award-info":[{"award-number":["81671593"]}],"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":["81971519"],"award-info":[{"award-number":["81971519"]}],"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":["82071819"],"award-info":[{"award-number":["82071819"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>T helper cells in patients with autoimmune disease of idiopathic inflammatory myopathies (IIM) are characterized with the proinflammatory phenotypes. The underlying mechanisms remain unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      RNA sequencing was performed for differential expression genes. Gene expression in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells was confirmed by quantitative real\u2010time PCR. CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells from IIM patients or healthy controls were evaluated for metabolic activities by Seahorse assay. Glucose uptake, T\u2010cell proliferation and differentiation were evaluated and measured by flow cytometry. Human CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells treated with iron chelators or\n                      <jats:italic>Pfkfb4<\/jats:italic>\n                      siRNA were measured for glucose metabolism, proliferation and differentiation. Signalling pathway activation was evaluated by western blot and flow cytometry. Mouse model of experimental autoimmune myositis (EAM) were induced and treated with iron chelator or rapamycin. CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cell differentiation and muscle inflammation in the EAM mice were evaluated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RNA\u2010sequencing analysis revealed that iron was involved with glucose metabolism and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cell differentiation. IIM patient\u2010derived CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells showed enhanced glycolysis and mitochondrial respiration, which was inhibited by iron chelation. CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells from patients with IIM was proinflammatory and iron chelation suppressed the differentiation of interferon gamma (IFN\u03b3)\u2010 and interleukin (IL)\u201017A\u2010producing CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells, which resulted in an increased percentage of regulatory T (Treg) cells. Mechanistically, iron promoted glucose metabolism by an upregulation of PFKFB4 through AKT\u2010mTOR signalling pathway. Notably, the knockdown of\n                      <jats:italic>Pfkfb4<\/jats:italic>\n                      decreased glucose influx and thus suppressed the differentiation of IFN\u03b3\u2010 and IL\u201017A\u2010producing CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells. In vivo, iron chelation inhibited mTOR signalling pathway and reduced PFKFB4 expression in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells, resulting in reduced proinflammatory IFN\u03b3\u2010 and IL\u201017A\u2010producing CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells and increased Foxp3\n                      <jats:sup>+<\/jats:sup>\n                      Treg cells, leading to ameliorated muscle inflammation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Iron directs CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells into a proinflammatory phenotype by enhancing glucose metabolism. Therapeutic targeting of iron metabolism should have the potential to normalize glucose metabolism in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T\u2010cells and reverse their proinflammatory phenotype in IIM.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.999","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T16:05:01Z","timestamp":1659456301000},"source":"Crossref","is-referenced-by-count":38,"title":["Iron controls T helper cell pathogenicity by promoting glucose metabolism in autoimmune myopathy"],"prefix":"10.1002","volume":"12","author":[{"given":"Yimei","family":"Lai","sequence":"first","affiliation":[{"name":"Department of Rheumatology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Rheumatology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binfeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuefang","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaohuan","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Rheumatology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Rheumatology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baokui","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Rheumatology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"},{"name":"Institute of Precision Medicine The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2624-5658","authenticated-orcid":false,"given":"Niansheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology The First Affiliated Hospital Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,2]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1402225"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2010.2"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/345347"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2010.07.006"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410160206"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2004.06144.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27465"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.11428"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-5728(03)00032-8"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2009.02.013"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0379-5"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095956"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.04.005"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.05.004"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003613"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2016.10.009"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.99"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2018.04.006"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa0835"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110278"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.714613"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.05.008"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/35042073"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3465"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02498"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2018.06.037"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2017.03.004"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.05.008"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22094591"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a030338"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12858"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2015.00001"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2018.00122"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12445"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0074450"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2990.1998.00092.x"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.12.034"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00010-19"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.1154"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.06.004"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.06.016"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3808"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41019"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-018-1095-7"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0291-z"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2009.04.014"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-020-1366-5"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI152345"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.64.070195.004055"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-11-0234"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2004.08.053"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2011.490"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40320"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780400928"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2020.102424"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts034"},{"key":"e_1_2_8_59_1","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.7035.1"},{"key":"e_1_2_8_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"e_1_2_8_61_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_2_8_62_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2009.080422"},{"key":"e_1_2_8_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-4328(01)00231-5"}],"container-title":["Clinical and Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.999","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ctm2.999","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ctm2.999","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,22]],"date-time":"2023-08-22T01:41:29Z","timestamp":1692668489000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ctm2.999"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8]]},"references-count":62,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2022,8]]}},"alternative-id":["10.1002\/ctm2.999"],"URL":"https:\/\/doi.org\/10.1002\/ctm2.999","archive":["Portico"],"relation":{},"ISSN":["2001-1326","2001-1326"],"issn-type":[{"value":"2001-1326","type":"print"},{"value":"2001-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8]]},"article-number":"e999"}}