{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T18:52:43Z","timestamp":1775242363474,"version":"3.50.1"},"reference-count":60,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"118","funder":[{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["102894\/Z\/13\/Z"],"award-info":[{"award-number":["102894\/Z\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome","doi-asserted-by":"publisher","award":["215612\/Z\/19\/Z"],"award-info":[{"award-number":["215612\/Z\/19\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["CRUK-OC-DPhil17-BM"],"award-info":[{"award-number":["CRUK-OC-DPhil17-BM"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["P300P3_155374"],"award-info":[{"award-number":["P300P3_155374"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF200C0059392"],"award-info":[{"award-number":["NNF200C0059392"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012331","name":"Leo Foundation","doi-asserted-by":"crossref","award":["LF18500"],"award-info":[{"award-number":["LF18500"]}],"id":[{"id":"10.13039\/501100012331","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Immunol."],"published-print":{"date-parts":[[2026,4,3]]},"abstract":"<jats:p>\n                    Tumor necrosis factor (TNF) orchestrates immune responses but can also drive inflammation-associated tissue damage. However, the mechanisms governing tissue tolerance to TNF remain poorly understood. Here, we reveal that TNF receptor 1 (TNFR1) abundance is regulated by two upstream open reading frames (uORFs) in the 5\u2032 untranslated region of\n                    <jats:italic toggle=\"yes\">TNFRSF1A<\/jats:italic>\n                    and demonstrate that this is a key determinant of TNF tolerance. uORF2 dominantly limits TNFR1 translation, and its disruption increases TNFR1 levels, leading to excessive TNF-induced gene activation and cell death in cell culture. By contrast, uORF1 dynamically regulates TNFR1 levels in response to inflammatory and stress signals. In mice, uORF2 protects against TNF-driven systemic inflammatory response syndrome and liver pathology. We additionally report that the translation of other immune receptor messenger RNAs, including\n                    <jats:italic toggle=\"yes\">TLR4<\/jats:italic>\n                    ,\n                    <jats:italic toggle=\"yes\">IFNAR1<\/jats:italic>\n                    , and\n                    <jats:italic toggle=\"yes\">IFNGR2<\/jats:italic>\n                    , is also controlled by uORFs. Thus, regulation of TNFR1 levels and possibly of other immune receptors emerges as a mechanism safeguarding against excessive immune responses and tissue damage.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.aeb6484","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T17:58:15Z","timestamp":1775239095000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Upstream ORFs control TNFR1 abundance and tissue tolerance to TNF"],"prefix":"10.1126","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3410-7303","authenticated-orcid":true,"given":"Biao","family":"Ma","sequence":"first","affiliation":[{"name":"Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK."},{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5941-1109","authenticated-orcid":true,"given":"Wenxin","family":"Lyu","sequence":"additional","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3352-5474","authenticated-orcid":true,"given":"John","family":"Rizk","sequence":"additional","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3905-1759","authenticated-orcid":true,"given":"Xiaoyue","family":"Han","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3511-2550","authenticated-orcid":true,"given":"Majken","family":"Kj\u00e6r","sequence":"additional","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3635-7787","authenticated-orcid":true,"given":"Vinnycius","family":"Pereira Almeida","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5929-0064","authenticated-orcid":true,"given":"Malin","family":"Jessen","sequence":"additional","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max Benjamin","family":"Sauerland","sequence":"additional","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1545-7228","authenticated-orcid":true,"given":"Carol Sze Ki","family":"Leung","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK."},{"name":"Centre for Immuno-Oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4995-3270","authenticated-orcid":true,"given":"Benoit J.","family":"Van den Eynde","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK."},{"name":"Ludwig Institute for Cancer Research, de Duve Institute, UCLouvain, Brussels, Belgium."},{"name":"WELBIO Department, WEL Research Institute, Brussels, Belgium."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6587-1152","authenticated-orcid":true,"given":"Xin","family":"Lu","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5641-5019","authenticated-orcid":true,"given":"Mads","family":"Gyrd-Hansen","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK."},{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1208623"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.09.001"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.022"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-023-01002-7"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.03.006"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00792-3"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.169"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1214935"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)37138-8"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1993.tb06197.x"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5488.2350"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1993.tb06157.x"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.025"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040435"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21093263"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.201400603"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.08890"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1283"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3208"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20156662"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx469"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01981-8"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0262"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.13328"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.69.7.4086-4094.1995"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2023.05.007"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.add6967"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.03464"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.483"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.09.020"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.11.025"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20092474"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e3182078843"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90134-C"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1177\/1753425909347508"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.20955"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.926175"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.06.023"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600998"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.299180"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E18-10-0628"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.03.021"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.103"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642195"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16260"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005288"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2015.11.013"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.11.016"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-06058-7"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.01.028"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80038-2"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.202317691"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.350752.123"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.01.019"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.350752.123"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.02.062"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.509"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx790"},{"key":"e_1_3_2_61_2","unstructured":"M. Gyrd-Hansen \u201cSchematic model of translational regulation of TNFR1 abundance via uORF2\u201d designed by Biao Ma. Created in BioRender (2026); https:\/\/BioRender.com\/3v85y9b."}],"container-title":["Science Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciimmunol.aeb6484","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T17:58:17Z","timestamp":1775239097000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciimmunol.aeb6484"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,3]]},"references-count":60,"journal-issue":{"issue":"118","published-print":{"date-parts":[[2026,4,3]]}},"alternative-id":["10.1126\/sciimmunol.aeb6484"],"URL":"https:\/\/doi.org\/10.1126\/sciimmunol.aeb6484","relation":{},"ISSN":["2470-9468"],"issn-type":[{"value":"2470-9468","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,3]]},"assertion":[{"value":"2025-08-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeb6484"}}