{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:31:51Z","timestamp":1792139511471,"version":"4.4.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T00:00:00Z","timestamp":1677628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Excessive levels of circulating proinflammatory mediators, known as \u201chypercytokinemia,\u201d that are generated by overwhelming immune system activation can lead to death due to critical organ failure and thrombotic events. Hypercytokinemia has been frequently associated with a variety of infectious and autoimmune diseases, with severe acute respiratory syndrome coronavirus 2 infection currently being the commonest cause, of what has been termed the cytokine storm. Among its various functions within the host, STING (stimulator of interferon genes) is critical in the defense against certain viruses and other pathogens. STING activation, particularly within cells of the innate immune system, triggers potent type I interferon and proinflammatory cytokine production. We thus hypothesized that generalized expression of a constitutively active STING mutant in mice would lead to hypercytokinemia. To test this, a Cre-loxP\u2013based system was used to cause the inducible expression of a constitutively active hSTING mutant (hSTING-N154S) in any tissue or cell type. Herein, we employed a tamoxifen-inducible ubiquitin C-CreERT2 transgenic to obtain generalized expression of the hSTING-N154S protein, thereby triggering the production of IFN-\u03b2 and multiple proinflammatory cytokines. This required euthanizing the mice within 3 to 4 d after tamoxifen administration. This preclinical model will allow for the rapid identification of compounds aimed at either preventing or ameliorating the lethal effects of hypercytokinemia.<\/jats:p>","DOI":"10.1093\/jleuko\/qiac019","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T13:16:15Z","timestamp":1677762975000},"page":"326-333","source":"Crossref","is-referenced-by-count":3,"title":["Inducible generalized activation of hSTING-N154S expression in mice leads to lethal hypercytokinemia: a model for \u201ccytokine storm\u201d"],"prefix":"10.1093","volume":"113","author":[{"given":"Gary R","family":"Martin","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"},{"name":"The McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Salazar Arcila","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"},{"name":"The McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J","family":"Hallihan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"},{"name":"The McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Scheidl-Yee","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"},{"name":"The McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank R","family":"Jirik","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"},{"name":"The McCaig Institute for Bone and Joint Health, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"},{"name":"The Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary , 3280 Hospital Drive Northwest, Calgary, Alberta , Canada T2N 4Z6"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,1]]},"reference":[{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1016\/j.chom.2020.04.009","article-title":"Complex immune dysregulation in COVID-19 patients with severe respiratory failure","volume":"27","author":"Giamarellos-Bourboulis","year":"2020","journal-title":"Cell Host Microbe"},{"issue":"7","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1136\/gutjnl-2020-321269","article-title":"COVID-19 and immunomodulation in IBD","volume":"69","author":"Neurath","year":"2020","journal-title":"Gut"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1038\/s41577-020-0311-8","article-title":"The Trinity of COVID-19: immunity, inflammation and intervention","volume":"20","author":"Tay","year":"2020","journal-title":"Nat Rev Immunol"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.jinf.2020.03.037","article-title":"The pathogenesis and treatment of the \u2018cytokine storm\u2019 in COVID-19","volume":"80","author":"Ye","year":"2020","journal-title":"J Infect"},{"issue":"2","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1007\/s11684-020-0773-x","article-title":"Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies","volume":"14","author":"Zhou","year":"2020","journal-title":"Front Med"},{"issue":"1","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00296-020-04636-y","article-title":"Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic","volume":"41","author":"Soy","year":"2021","journal-title":"Rheumatol Int"},{"issue":"1","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.immuni.2020.06.017","article-title":"Cytokine storms: understanding COVID-19","volume":"53","author":"Mangalmurti","year":"2020","journal-title":"Immunity"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"e46","DOI":"10.1016\/S2213-2600(20)30216-2","article-title":"COVID-19 cytokine storm: the interplay between inflammation and coagulation","volume":"8","author":"Jose","year":"2020","journal-title":"Lancet Respir Med"},{"issue":"1","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1136\/annrheumdis-2020-218323","article-title":"Preliminary predictive criteria for COVID-19 cytokine storm","volume":"80","author":"Caricchio","year":"2021","journal-title":"Ann Rheum Dis"},{"issue":"4","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1016\/j.cell.2020.09.016","article-title":"The immunology of multisystem inflammatory syndrome in children with COVID-19","volume":"183","author":"Consiglio","year":"2020","journal-title":"Cell"},{"key":"2023030207323886300_","first-page":"51","article-title":"Multi-system inflammatory syndrome in children & adolescents (MIS-C): a systematic review of clinical features and presentation","volume":"38","author":"Radia","year":"2021","journal-title":"Paediatr Respir Rev"},{"issue":"3","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1084\/jem.20050828","article-title":"Multiple organ infection and the pathogenesis of SARS","volume":"202","author":"Gu","year":"2005","journal-title":"J Exp Med"},{"key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.thromres.2020.04.013","article-title":"Incidence of thrombotic complications in critically ill ICU patients with COVID-19","volume":"191","author":"Klok","year":"2020","journal-title":"Thromb Res"},{"issue":"4","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.chom.2020.02.004","article-title":"TMEM173 drives lethal coagulation in sepsis","volume":"27","author":"Zhang","year":"2020","journal-title":"Cell Host Microbe"},{"issue":"10","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1038\/s41584-020-0474-5","article-title":"Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications","volume":"16","author":"Merrill","year":"2020","journal-title":"Nat Rev Rheumatol"},{"issue":"11","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1182\/blood.2020007938","article-title":"Postdischarge thrombosis and hemorrhage in patients with COVID-19","volume":"136","author":"Patell","year":"2020","journal-title":"Blood"},{"issue":"10223","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","article-title":"Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China","volume":"395","author":"Huang","year":"2020","journal-title":"Lancet"},{"issue":"5","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1002\/acr2.11140","article-title":"Intravenous anakinra for macrophage activation syndrome may hold lessons for treatment of cytokine storm in the setting of coronavirus disease 2019","volume":"2","author":"Wampler Muskardin","year":"2020","journal-title":"ACR Open Rheumatol"},{"key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"110825","DOI":"10.1016\/j.biopha.2020.110825","article-title":"Tocilizumab combined with favipiravir in the treatment of COVID-19: a multicenter trial in a small sample size","volume":"133","author":"Zhao","year":"2021","journal-title":"Biomed Pharmacother"},{"issue":"11","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1038\/s41576-019-0151-1","article-title":"DNA sensing by the cGAS-STING pathway in health and disease","volume":"20","author":"Motwani","year":"2019","journal-title":"Nat Rev Genet"},{"issue":"1","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1146\/annurev-micro-102215-095605","article-title":"Detection of microbial infections through innate immune sensing of nucleic acids","volume":"72","author":"Tan","year":"2018","journal-title":"Annu Rev Microbiol"},{"issue":"6431","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"aat8657","DOI":"10.1126\/science.aat8657","article-title":"cGAS in action: expanding roles in immunity and inflammation","volume":"363","author":"Ablasser","year":"2019","journal-title":"Science"},{"issue":"5","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.cell.2013.08.014","article-title":"Cyclic dinucleotides and the innate immune response","volume":"154","author":"Danilchanka","year":"2013","journal-title":"Cell"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"e99988","DOI":"10.1371\/journal.pone.0099988","article-title":"DMXAA causes tumor site-specific vascular disruption in murine non-small cell lung cancer, and like the endogenous non-canonical cyclic dinucleotide STING agonist, 2\u20323\u2032-cGAMP, induces M2 macrophage repolarization","volume":"9","author":"Downey","year":"2014","journal-title":"PLoS One"},{"issue":"1","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"14281","DOI":"10.1038\/s41598-019-50656-5","article-title":"Stimulator of interferon genes (STING) activation exacerbates experimental colitis in mice","volume":"9","author":"Martin","year":"2019","journal-title":"Sci Rep"},{"issue":"7485","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/nature12862","article-title":"Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity","volume":"505","author":"Schoggins","year":"2014","journal-title":"Nature"},{"issue":"1","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/ni.2491","article-title":"STING and the innate immune response to nucleic acids in the cytosol","volume":"14","author":"Burdette","year":"2013","journal-title":"Nat Immunol"},{"issue":"9","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"E2058","DOI":"10.1073\/pnas.1716937115","article-title":"STING-dependent translation inhibition restricts RNA virus replication","volume":"115","author":"Franz","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.cytogfr.2014.08.004","article-title":"Message in a bottle: lessons learned from antagonism of STING signalling during RNA virus infection","volume":"25","author":"Maringer","year":"2014","journal-title":"Cytokine Growth Factor Rev"},{"issue":"2","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"e30802","DOI":"10.1371\/journal.pone.0030802","article-title":"Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling","volume":"7","author":"Sun","year":"2012","journal-title":"PLoS One"},{"issue":"3","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.chom.2018.01.006","article-title":"Dampened STING-dependent interferon activation in bats","volume":"23","author":"Xie","year":"2018","journal-title":"Cell Host Microbe"},{"issue":"7899","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41586-022-04421-w","article-title":"The cGAS-STING pathway drives type I IFN immunopathology in COVID-19","volume":"603","author":"Domizio","year":"2022","journal-title":"Nature"},{"issue":"10","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"4779","DOI":"10.4049\/jimmunol.1402051","article-title":"Cutting edge: sTING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation","volume":"193","author":"Zhu","year":"2014","journal-title":"J Immunol"},{"issue":"47","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"19386","DOI":"10.1073\/pnas.1215006109","article-title":"STING manifests self DNA-dependent inflammatory disease","volume":"109","author":"Ahn","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"5226","DOI":"10.1038\/s41467-018-07425-1","article-title":"STING-dependent sensing of self-DNA drives silica-induced lung inflammation","volume":"9","author":"Benmerzoug","year":"2018","journal-title":"Nat Commun"},{"issue":"2","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/j.jaci.2018.04.034","article-title":"Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M\/wild-type mice","volume":"143","author":"Bouis","year":"2019","journal-title":"J Allergy Clin Immunol"},{"issue":"3","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"e13194","DOI":"10.1111\/apha.13194","article-title":"The emerging role of stimulator of interferons genes signaling in sepsis: inflammation, autophagy, and cell death","volume":"225","author":"Hu","year":"2019","journal-title":"Acta Physiol (Oxf)"},{"issue":"3","key":"2023030207323886300_","doi-asserted-by":"crossref","DOI":"10.26508\/lsa.201800215","article-title":"Expression of a constitutively active human STING mutant in hematopoietic cells produces an Ifnar1-dependent vasculopathy in mice","volume":"2","author":"Martin","year":"2019","journal-title":"Life Sci Alliance"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1056\/NEJMoa1312625","article-title":"Activated STING in a vascular and pulmonary syndrome","volume":"371","author":"Liu","year":"2014","journal-title":"N Engl J Med"},{"issue":"5","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1097\/SHK.0000000000000771","article-title":"STING and TRIF contribute to mouse sepsis, depending on severity of the disease model","volume":"47","author":"Heipertz","year":"2017","journal-title":"Shock"},{"issue":"412","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"aan5689","DOI":"10.1126\/scitranslmed.aan5689","article-title":"ALK is a therapeutic target for lethal sepsis","volume":"9","author":"Zeng","year":"2017","journal-title":"Sci Transl Med"},{"key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.ebiom.2019.02.055","article-title":"STING-mediated intestinal barrier dysfunction contributes to lethal sepsis","volume":"41","author":"Hu","year":"2019","journal-title":"EBioMedicine"},{"issue":"1","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nn.2467","article-title":"A robust and high-throughput cre reporting and characterization system for the whole mouse brain","volume":"13","author":"Madisen","year":"2010","journal-title":"Nat Neurosci"},{"issue":"1","key":"2023030207323886300_","first-page":"pdb.prot4398","article-title":"Preparing mouse embryo fibroblasts","volume":"2006","author":"Nagy","year":"2006","journal-title":"CSH Protoc"},{"issue":"1","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s13045-018-0653-x","article-title":"Cytokine release syndrome: grading, modeling, and new therapy","volume":"11","author":"Liu","year":"2018","journal-title":"J Hematol Oncol"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/s41591-018-0036-4","article-title":"Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells","volume":"24","author":"Norelli","year":"2018","journal-title":"Nat Med"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/s41591-018-0041-7","article-title":"CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade","volume":"24","author":"Giavridis","year":"2018","journal-title":"Nat Med"},{"issue":"23","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"2255","DOI":"10.1056\/NEJMra2026131","article-title":"Cytokine storm","volume":"383","author":"Fajgenbaum","year":"2020","journal-title":"N Engl J Med"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1038\/s41591-020-0901-9","article-title":"Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19","volume":"26","author":"Liao","year":"2020","journal-title":"Nat Med"},{"issue":"8","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1056\/NEJMoa2021436","article-title":"Dexamethasone in hospitalized patients with COVID-19","volume":"384","author":"RECOVERY Collaborative Group","year":"2021","journal-title":"N Engl J Med. Feb"},{"issue":"6","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1182\/blood.2020006075","article-title":"JAK\/STAT pathway inhibition sensitizes CD8 T cells to dexamethasone-induced apoptosis in hyperinflammation","volume":"136","author":"Meyer","year":"2020","journal-title":"Blood"},{"issue":"12","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.3390\/antibiotics10121507","article-title":"A closer look at dexamethasone and the SARS-CoV-2-induced cytokine storm: in silico insights of the first life-saving COVID-19 drug","volume":"10","author":"Morgan","year":"2021","journal-title":"Antibiotics (Basel)"},{"issue":"3","key":"2023030207323886300_","doi-asserted-by":"crossref","first-page":"318","DOI":"10.3390\/cells11030318","article-title":"Lung inflammation in STING-associated vasculopathy with onset in infancy (SAVI)","volume":"11","author":"David","year":"2022","journal-title":"Cells"}],"container-title":["Journal of Leukocyte Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/113\/3\/326\/49394258\/qiac019.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/113\/3\/326\/49394258\/qiac019.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,27]],"date-time":"2023-03-27T05:20:36Z","timestamp":1679894436000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jleukbio\/article\/113\/3\/326\/7067168"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,1]]},"references-count":53,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3,1]]},"published-print":{"date-parts":[[2023,3,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jleuko\/qiac019","relation":{},"ISSN":["1938-3673"],"issn-type":[{"value":"1938-3673","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,3,1]]},"published":{"date-parts":[[2023,3,1]]}}}