{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T21:52:40Z","timestamp":1785275560451,"version":"3.55.0"},"reference-count":35,"publisher":"Wiley","license":[{"start":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T00:00:00Z","timestamp":1642377600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003621","name":"Ministry of Science, ICT and Future Planning","doi-asserted-by":"publisher","award":["NRF-2017R1A2B3006406"],"award-info":[{"award-number":["NRF-2017R1A2B3006406"]}],"id":[{"id":"10.13039\/501100003621","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Immunology Research"],"published-print":{"date-parts":[[2022,1,17]]},"abstract":"<jats:p>Iron plays an important role in macrophage polarization by altering metabolic and redox status. However, the impact of iron on the immune status of macrophages is still controversial. In this study, we report that ferric ammonium citrate (FAC) upregulates PD-L1 expression in macrophages. FAC not only altered the phenotype of macrophages but also led to enriching immune-modulatory T cell subsets. Since iron is known to be a constituent of coenzymes facilitating metabolic processes in mitochondria, we examined the metabolic status of FAC-overloaded macrophages by measuring the oxygen consumption rate (OCR) and the represented coenzyme, aconitase. In addition to enhancement of metabolic processes, FAC accelerated the Fenton reaction in macrophages, which also contributed to the facilitation of oxygen consumption. We reasoned that the enhancement of the OCR leads to the production of reactive oxygen species (ROS), which are directly linked to PD-L1 induction. Using ferrostatin, rotenone, and N-acetyl-L-cysteine, we confirmed that metabolic and redox regulation is responsible for FAC-mediated PD-L1 expression. Furthermore, we suggested that FAC-induced ROS production may explain FAC-mediated pro- and anti-inflammatory responses in macrophages. These findings may extend our understanding of regulating iron concentration during immune checkpoint therapy in cancer patients.<\/jats:p>","DOI":"10.1155\/2022\/6284124","type":"journal-article","created":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T15:20:17Z","timestamp":1642432817000},"page":"1-8","source":"Crossref","is-referenced-by-count":12,"title":["Ferric Ammonium Citrate Upregulates PD-L1 Expression through Generation of Reactive Oxygen Species"],"prefix":"10.1155","volume":"2022","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1881-9869","authenticated-orcid":true,"given":"Eun Jung","family":"Choi","sequence":"first","affiliation":[{"name":"Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41404, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4368-1390","authenticated-orcid":true,"given":"Chang Hyun","family":"Jeon","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, School of Medicine, Kyungpook National University, Daegu 41566, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2261-7269","authenticated-orcid":true,"given":"In-Kyu","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41404, Republic of Korea"},{"name":"Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41944, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12034"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151159"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.04.004"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.14348\/molcells.2020.0198"},{"key":"5","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.03.001"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00141"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.15.4674"},{"key":"8","doi-asserted-by":"publisher","DOI":"10.1023\/b:mcbi.0000044395.59739.1f"},{"key":"9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagrm.2014.07.013"},{"key":"10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00420"},{"key":"11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.01.006"},{"key":"12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92167"},{"key":"13","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2021.112575"},{"key":"14","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000001653"},{"key":"15","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14433-7"},{"key":"16","doi-asserted-by":"publisher","DOI":"10.3390\/ph11040137"},{"key":"17","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15682"},{"key":"18","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2009.05.004"},{"key":"19","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-020-01494-3"},{"key":"20","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2019.4188"},{"key":"21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2017.05.019"},{"key":"22","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0196921"},{"key":"23","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3A0318-108R"},{"key":"24","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2015.11.002"},{"key":"25","doi-asserted-by":"publisher","DOI":"10.1038\/s41421-018-0013-6"},{"key":"26","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2016.34"},{"key":"27","doi-asserted-by":"publisher","DOI":"10.1164\/arrd.1986.133.1.78"},{"key":"28","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22094591"},{"key":"29","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20133328"},{"key":"30","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20090847"},{"key":"31","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00834-9"},{"key":"32","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.112813"},{"key":"33","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2019.102837"},{"key":"34","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.584477"},{"key":"35","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr.2019.08.09"}],"container-title":["Journal of Immunology Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/jir\/2022\/6284124.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/jir\/2022\/6284124.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/jir\/2022\/6284124.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T15:20:21Z","timestamp":1642432821000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.hindawi.com\/journals\/jir\/2022\/6284124\/"}},"subtitle":[],"editor":[{"given":"Daniele","family":"Maria-Ferreira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,1,17]]},"references-count":35,"alternative-id":["6284124","6284124"],"URL":"https:\/\/doi.org\/10.1155\/2022\/6284124","relation":{},"ISSN":["2314-7156","2314-8861"],"issn-type":[{"value":"2314-7156","type":"electronic"},{"value":"2314-8861","type":"print"}],"subject":[],"published":{"date-parts":[[2022,1,17]]}}}