{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T12:18:12Z","timestamp":1793017092971,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Severe burns can lead to systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS) due to inflammation-immunity dysregulation. This study aimed to identify key immune-related molecules and potential drugs for immune regulation in severe burn treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Method<\/jats:title><jats:p>Microarray datasets GSE77791 and GSE37069 were analyzed to identify immune-related differentially expressed genes (DEGs), enriched pathways and prognosis-related genes. The DGIdb database was used to identify potentially clinically relevant small molecular drugs for hub DEGs. Hub DEGs were validated by total RNA from clinical blood samples through qPCR. The efficacy of drug candidates was tested in a severe burn mouse model. Pathologic staining was used to observe organ damage. Enzyme Linked Immunosorbent Assay (ELISA) was used to detect the serum IL-1b, IL-6, TNF-a and MCP-1 contents. Activation of the NF-\u03baB inflammatory pathway was detected by western blotting. Transcriptome sequencing was used to observe inflammatory-immune responses in the lung.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 113 immune-related DEGs were identified, and the presence of immune overactivation was confirmed in severe burns. S100A8 was not only significantly upregulated and identified to be prognosis-related among the hub DEGs but also exhibited an increasing trend in clinical blood samples. Methotrexate, which targets S100A8, as predicted by the DGIdb, significantly reduces transcription level of S100A8 and inflammatory cytokine content in blood, organ damage (lungs, liver, spleen, and kidneys) and mortality in severely burned mice when combined with fluid resuscitation. The inflammatory-immune response was suppressed in the lungs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>S100A8 with high transcription level in blood is a potential biomarker for poor severe burn prognosis. It suggested that methotrexate has a potential application in severe burn immunotherapy. Besides, it should be emphasized that fluid resuscitation is necessary for the function of methotrexate.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1455899","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T04:31:55Z","timestamp":1725597115000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Suppression of overactivated immunity in the early stage is the key to improve the prognosis in severe burns"],"prefix":"10.3389","volume":"15","author":[{"given":"Yang","family":"Xiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo-han","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-qiu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin-hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian-sheng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing-feng","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shi-hui","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41572-020-0145-5","article-title":"Burn injury","volume":"6","author":"Jeschke","year":"2020","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/SLA.0000000000000764","article-title":"Simvastatin reduces burn injury-induced splenic apoptosis via downregulation of the TNF-alpha\/NF-kappaB pathway","volume":"261","author":"Zhao","year":"2015","journal-title":"Ann Surg"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01481","article-title":"Pediatric burn survivors have long-term immune dysfunction with diminished vaccine response","volume":"11","author":"Johnson","year":"2020","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s41038-017-0073-0","article-title":"The influence of metabolic imbalances and oxidative stress on the outcome of critically ill polytrauma patients: a review","volume":"5","author":"Rogobete","year":"2017","journal-title":"Burns Trauma"},{"key":"B5","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.ccc.2016.06.001","article-title":"The physiologic basis of burn shock and the need for aggressive fluid resuscitation","volume":"32","author":"Rae","year":"2016","journal-title":"Crit Care Clin"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000001795","article-title":"Myeloid-derived suppressor cells (MDSCs) and the immunoinflammatory response to injury (Mini review)","volume":"56","author":"Sayyadioskoie","year":"2021","journal-title":"Shock"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2119\/molmed.2010.00178","article-title":"A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma","volume":"17","author":"Cuenca","year":"2011","journal-title":"Mol Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1186\/s12943-023-01885-w","article-title":"Exploiting innate immunity for cancer immunotherapy","volume":"22","author":"Yi","year":"2023","journal-title":"Mol Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nri2506","article-title":"Myeloid-derived suppressor cells as regulators of the immune system","volume":"9","author":"Gabrilovich","year":"2009","journal-title":"Nat Rev Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01918","article-title":"The critical roles and mechanisms of immune cell death in sepsis","volume":"11","author":"Cheng","year":"2020","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"13469","DOI":"10.3390\/ijms241713469","article-title":"Neutrophils and the systemic inflammatory response syndrome (SIRS)","volume":"24","author":"Sikora","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","first-page":"17583","DOI":"10.3390\/ijms242417583","article-title":"How neutrophils shape the immune response: reassessing their multifaceted role in health and disease","volume":"24","author":"Shafqat","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1807442","article-title":"Management of burns","volume":"380","author":"Greenhalgh","year":"2019","journal-title":"N Engl J Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1089\/sur.2020.104","article-title":"Novel therapeutics for the treatment of burn infection","volume":"22","author":"Salyer","year":"2021","journal-title":"Surg Infect (Larchmt)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/trf.15243","article-title":"Plasma for burn shock resuscitation: is it time to go back to the future","volume":"59","author":"Gurney","year":"2019","journal-title":"Transfusion"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1097\/01.shk.0000209564.84822.f2","article-title":"The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies","volume":"26","author":"Cotton","year":"2006","journal-title":"Shock"},{"key":"B17","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/s40560-014-0051-6","article-title":"Efficacy of antithrombin in preclinical and clinical applications for sepsis-associated disseminated intravascular coagulation","volume":"2","author":"Iba","year":"2014","journal-title":"J Intensive Care"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.issn.1009-2587.2016.06.009","article-title":"Effects of ulinastatin on immune function of patients with severe burn injury","volume":"32","author":"Li","year":"2016","journal-title":"Zhonghua Shao Shang Za Zhi"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e12680","DOI":"10.7717\/peerj.12680","article-title":"Identifying changes in immune cells and constructing prognostic models using immune-related genes in post-burn immunosuppression","volume":"10","author":"Wang","year":"2022","journal-title":"PeerJ"},{"key":"B20","doi-asserted-by":"publisher","first-page":"tkac050","DOI":"10.1093\/burnst\/tkac050","article-title":"Prospective study and validation of early warning marker discovery based on integrating multi-omics analysis in severe burn patients with sepsis","volume":"11","author":"Huang","year":"2023","journal-title":"Burns Trauma"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2015.12.075","article-title":"Artemisinin protects mice against burn sepsis through inhibiting NLRP3 inflammasome activation","volume":"34","author":"Long","year":"2016","journal-title":"Am J Emerg Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.cyto.2013.04.002","article-title":"Blocking TNF-\u03b1 enhances Pseudomonas aeruginosa-induced mortality in burn mice through induction of IL-1\u03b2","volume":"63","author":"Tsay","year":"2013","journal-title":"Cytokine"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.burns.2024.05.009","article-title":"1,25-Dihydroxyvitamin D3 reduces early mortality post severe burn injury via alleviating endotoxemia, oxidative stress and inflammation","volume":"8","author":"Chen","year":"2024","journal-title":"Burns"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1113948","article-title":"Murine scald models characterize the role of neutrophils and neutrophil extracellular traps in severe burns","volume":"14","author":"Elrod","year":"2023","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1097\/BCR.0b013e3181a28e37","article-title":"Rosiglitazone, a PPAR-gamma ligand, reduces burn progression in rats","volume":"30","author":"Taira","year":"2009","journal-title":"J Burn Care Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/s40779-022-00422-y","article-title":"Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options","volume":"9","author":"Liu","year":"2022","journal-title":"Mil Med Res"},{"key":"B27","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s13054-021-03862-5","article-title":"Biomarkers for sepsis: more than just fever and leukocytosis-a narrative review","volume":"26","author":"Barichello","year":"2022","journal-title":"Crit Care"},{"key":"B28","doi-asserted-by":"publisher","first-page":"180015","DOI":"10.1038\/sdata.2018.15","article-title":"ImmPort, toward repurposing of open access immunological assay data for translational and clinical research","volume":"5","author":"Bhattacharya","year":"2018","journal-title":"Sci Data"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1147","article-title":"InnateDB: systems biology of innate immunity and beyond\u2013recent updates and continuing curation","volume":"41","author":"Breuer","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"B33","doi-asserted-by":"publisher","first-page":"13","DOI":"10.4137\/CIN.S13495","article-title":"OmicCircos: A simple-to-use R package for the circular visualization of multidimensional omics data","volume":"13","author":"Hu","year":"2014","journal-title":"Cancer Inform"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku1003","article-title":"STRING v10: protein-protein interaction networks, integrated over the tree of life","volume":"43","author":"Szklarczyk","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1143","article-title":"DGIdb 3.0: a redesign and expansion of the drug-gene interaction database","volume":"46","author":"Cotto","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B36","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1186\/s13148-019-0730-1","article-title":"Statistical predictions with glmnet","volume":"11","author":"Engebretsen","year":"2019","journal-title":"Clin Epigenet"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.681525","article-title":"Anti-inflammatory and pro-apoptotic effects of 18beta-glycyrrhetinic acid in vitro and in vivo models of rheumatoid arthritis","volume":"12","author":"Feng","year":"2021","journal-title":"Front Pharmacol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"108666","DOI":"10.1016\/j.biopha.2019.108666","article-title":"G protein-coupled estrogen receptor activation improves contractile and diastolic functions in rat renal interlobular artery to protect against renal ischemia reperfusion injury","volume":"112","author":"Chang","year":"2019","journal-title":"BioMed Pharmacother"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/hep.32204","article-title":"Cirrhosis regression is associated with improved clinical outcomes in patients with nonalcoholic steatohepatitis","volume":"75","author":"Sanyal","year":"2022","journal-title":"Hepatology"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.903859","article-title":"Extracellular CIRP promotes GPX4-mediated ferroptosis in sepsis","volume":"13","author":"Shimizu","year":"2022","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkl084","article-title":"Clarithromycin is an effective immunomodulator in experimental pyelonephritis caused by pan-resistant Klebsiella pneumoniae","volume":"57","author":"Giamarellos-Bourboulis","year":"2006","journal-title":"J Antimicrob Chemother"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2011.06.012","article-title":"Jack of all trades: pleiotropy and the application of chemically modified tetracycline-3 in sepsis and the acute respiratory distress syndrome (ARDS)","volume":"64","author":"Roy","year":"2011","journal-title":"Pharmacol Res"},{"key":"B43","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/j.immuni.2019.10.010","article-title":"Tissue-specific macrophage responses to remote injury impact the outcome of subsequent local immune challenge","volume":"51","author":"Hoyer","year":"2019","journal-title":"Immunity"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.3390\/vaccines11121813","article-title":"COVID-19 vaccination and immunosuppressive therapy in immune-mediated inflammatory diseases","volume":"11","author":"Serra Lopez-Matencio","year":"2023","journal-title":"Vaccines (Basel)"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1080\/14656566.2023.2297798","article-title":"Advances in non-biological drugs for the treatment of rheumatoid arthritis","volume":"25","author":"Venetsanopoulou","year":"2023","journal-title":"Expert Opin Pharmacother"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1126\/science.adn1011","article-title":"Oxygen imaging of hypoxic pockets in the mouse cerebral cortex","volume":"383","author":"Beinlich","year":"2024","journal-title":"Science"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1455899\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T04:32:00Z","timestamp":1725597120000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1455899\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,6]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2024.1455899"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1455899","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,6]]},"article-number":"1455899"}}