{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:21:15Z","timestamp":1787509275448,"version":"build-2736575974"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"26","license":[{"start":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T00:00:00Z","timestamp":1718841600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2021R1C1C2006896"],"award-info":[{"award-number":["2021R1C1C2006896"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003716","name":"Korea Basic Science Institute","doi-asserted-by":"publisher","award":["2022R1A6C101A751"],"award-info":[{"award-number":["2022R1A6C101A751"]}],"id":[{"id":"10.13039\/501100003716","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2021R1A2C4001704"],"award-info":[{"award-number":["2021R1A2C4001704"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2021R1C1C1009508"],"award-info":[{"award-number":["2021R1C1C1009508"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1A4A3078645"],"award-info":[{"award-number":["2020R1A4A3078645"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2021R1A2B5B02086828"],"award-info":[{"award-number":["2021R1A2B5B02086828"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,6,25]]},"abstract":"<jats:p>Thymocyte selection\u2013associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX\u2013RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.<\/jats:p>","DOI":"10.1073\/pnas.2319322121","type":"journal-article","created":{"date-parts":[[2024,6,20]],"date-time":"2024-06-20T13:40:46Z","timestamp":1718890846000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":9,"title":["The TOX\u2013RAGE axis mediates inflammatory activation and lung injury in severe pulmonary infectious diseases"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9143-7202","authenticated-orcid":false,"given":"Hyelim","family":"Kim","sequence":"first","affiliation":[{"name":"Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea"},{"name":"Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1498-5624","authenticated-orcid":false,"given":"Hee Ho","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Hanyang University, Seoul 04763, Republic of Korea"},{"name":"Research Institute for Convergence of Basic Science, Hanyang University, Seoul 04763, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0329-0029","authenticated-orcid":false,"given":"Hong Nam","family":"Kim","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea"},{"name":"Division of Bio-Medical Science and Technology (Korea Institute of Science and Technology School), Korea University of Science and Technology, Seoul 02792, Republic of Korea"},{"name":"School of Mechanical Engineering, Yonsei University, Seoul 03722, Republic of Korea"},{"name":"Yonsei-Korea Institute of Science and Technology Convergence Research Institute, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7802-9435","authenticated-orcid":false,"given":"Donghyuk","family":"Seo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Soo","family":"Hong","sequence":"additional","affiliation":[{"name":"Division of Pulmonology and Allergy, Department of Internal Medicine, College of Medicine, Yeungnam University and Regional Center for Respiratory Diseases, Yeungnam University Medical Center, Daegu 42415, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jong Geol","family":"Jang","sequence":"additional","affiliation":[{"name":"Division of Pulmonology and Allergy, Department of Internal Medicine, College of Medicine, Yeungnam University and Regional Center for Respiratory Diseases, Yeungnam University Medical Center, Daegu 42415, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun U","family":"Seo","sequence":"additional","affiliation":[{"name":"Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea"},{"name":"Division of Bio-Medical Science and Technology (Korea Institute of Science and Technology School), Korea University of Science and Technology, Seoul 02792, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Young","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boram","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Hanyang University, Seoul 04763, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Woo","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wantae","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Life Science, University of Seoul, Seoul 02504, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7104-8325","authenticated-orcid":false,"given":"June Hong","family":"Ahn","sequence":"additional","affiliation":[{"name":"Division of Pulmonology and Allergy, Department of Internal Medicine, College of Medicine, Yeungnam University and Regional Center for Respiratory Diseases, Yeungnam University Medical Center, Daegu 42415, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4336-5221","authenticated-orcid":false,"given":"Wonhwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,6,20]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30183-5"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30165-X"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0820-9"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15562-9"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30628-0"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abb8925"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2015432"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvaa106"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30937-5"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc6027"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc8511"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abc1564"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01531-2020"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-00292-7"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.04.011"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2332-7"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2179-y"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-020-0290-0"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01461"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abl4784"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1325-x"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1324-y"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3168"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-021-00275-y"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.150744"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI18058"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.04.042"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3168"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2011.12.001"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1930"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni767"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1326-9"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1325-x"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2020.102763"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-07638-2"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.03.009"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-016-0460-2"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mehy.2020.109950"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1097\/01.CCM.0000155991.88802.4D"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.08.016"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.09.021"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.media.2021.102105"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.3346\/jkms.2021.36.e46"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-08-519520"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-013-1081-6"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/adma.201503093"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2319322121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,2]],"date-time":"2024-07-02T11:22:50Z","timestamp":1719919370000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2319322121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,20]]},"references-count":46,"journal-issue":{"issue":"26","published-print":{"date-parts":[[2024,6,25]]}},"alternative-id":["10.1073\/pnas.2319322121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2319322121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,20]]},"assertion":[{"value":"2023-11-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2319322121"}}