{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T02:23:48Z","timestamp":1794277428037,"version":"4.9.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"\n Objectives<\/jats:title>\n \n An important pathogenic role for neutrophils in systemic lupus erythematosus (SLE) has been proposed. Neutrophils that lack brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (\n Bmal1<\/jats:italic>\n ), one of the clock genes, are defective in aging and proinflammatory responses. We assessed the role of\n Bmal1<\/jats:italic>\n in clinical and immunologic manifestations of murine lupus and in human SLE neutrophils.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Myeloid-conditional\n Bmal1<\/jats:italic>\n knockout mice (\n \n Bmal1\n Mye\u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n ) and wild type (WT) were treated with epicutaneous TLR7\/8 agonist (imiquimod; IMQ) for 6 weeks to induce a lupus phenotype. Upon euthanasia, immune responses, autoantibodies and renal manifestations were evaluated. NET formation and gene expression of bone marrow (BM)-derived murine neutrophils were evaluated.\n BMAL1<\/jats:italic>\n expression was quantified in SLE neutrophils and compared with clinical disease.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n IMQ-treated\n \n Bmal1\n Mye\u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n and WT displayed comparable systemic inflammation. While renal function did not differ, serum anti-dsDNA levels and renal immune complex deposition were significantly increased in\n \n Bmal1\n Mye\u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n . While no differences were observed in NET formation, expression levels of\n April<\/jats:italic>\n in BM neutrophils were significantly higher in\n \n Bmal1\n Mye\u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n . Bulk RNA-sequence data showed that BM neutrophils in IMQ-treated\n \n Bmal1\n Mye\u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n were relatively immature when compared with IMQ-treated WT. BM showed an enhanced April protein expression in\n \n Bmal1\n Mye\u2212\/\u2212<\/jats:sup>\n <\/jats:italic>\n mice.\n BMAL1<\/jats:italic>\n levels in human SLE peripheral blood neutrophils correlated positively with serum C3 and negatively with serum anti-dsDNA levels.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Bmal1<\/jats:italic>\n is associated with lower disease activity in SLE. These results indicate that perturbation in the circadian rhythm of neutrophils can have pathogenic consequences in SLE.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2024.1465185","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T01:34:16Z","timestamp":1732671256000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["The circadian clock gene BMAL1 modulates autoimmunity features in lupus"],"prefix":"10.3389","volume":"15","author":[{"given":"Shuichiro","family":"Nakabo","sequence":"first","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH)","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donavon","family":"Sandoval-Heglund","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH)","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Hanata","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH)","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Brooks","sequence":"additional","affiliation":[{"name":"Biodata Mining and Discovery Section, NIAMS, NIH","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Division of Veterinary Resources, NIH","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingzeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH)","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William G.","family":"Ambler","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH)","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zerai","family":"Manna","sequence":"additional","affiliation":[{"name":"Lupus Clinical Trials Unit, NIAMS, NIH","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Poncio","sequence":"additional","affiliation":[{"name":"Lupus Clinical Trials Unit, NIAMS, NIH","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarfaraz","family":"Hasni","sequence":"additional","affiliation":[{"name":"Lupus Clinical Trials Unit, NIAMS, NIH","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamima","family":"Islam","sequence":"additional","affiliation":[{"name":"Genomic Technology Section, Office of Science and Technology, NIAMS, NIH","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Dell\u2019Orso","sequence":"additional","affiliation":[{"name":"Genomic Technology Section, Office of Science and Technology, NIAMS, NIH","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana J.","family":"Kaplan","sequence":"additional","affiliation":[{"name":"Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH)","place":["Bethesda, MD, United States"]},{"name":"Lupus Clinical Trials Unit, NIAMS, NIH","place":["Bethesda, MD, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00787-0","article-title":"Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases","volume":"23","author":"Wigerblad","year":"2023","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302112","article-title":"Neutrophil-mediated IFN activation in the bone marrow alters B cell development in human and murine systemic lupus erythematosus","volume":"192","author":"Palanichamy","year":"2014","journal-title":"J Immunol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1016\/j.immuni.2019.01.002","article-title":"A neutrophil timer coordinates immune defense and vascular protection","volume":"50","author":"Adrover","year":"2019","journal-title":"Immunity"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01827","article-title":"Fatigue, sleep, and autoimmune and related disorders","volume":"10","author":"Zielinski","year":"2019","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00186.2006","article-title":"Effects of sleep deprivation on the development of autoimmune disease in an experimental model of systemic lupus erythematosus","volume":"291","author":"Palma","year":"2006","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1177\/0961203318778368","article-title":"Less than 7 hours of sleep per night is associated with transitioning to systemic lupus erythematosus","volume":"27","author":"Young","year":"2018","journal-title":"Lupus"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/acr.25017","article-title":"Association of sleep deprivation and the risk of developing systemic lupus Erythematosus among women","volume":"75","author":"Choi","year":"2023","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B8","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1002\/art.38298","article-title":"Epicutaneous application of toll-like receptor 7 agonists leads to systemic autoimmunity in wild-type mice: a new model of systemic Lupus erythematosus","volume":"66","author":"Yokogawa","year":"2014","journal-title":"Arthritis Rheumatol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1681\/ASN.2012080838","article-title":"Genetic analysis of mesangial matrix expansion in aging mice and identification of Far2 as a candidate gene","volume":"24","author":"Noordmans","year":"2013","journal-title":"J Am Soc Nephrol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1916897117","article-title":"Interferon lambda promotes immune dysregulation and tissue inflammation in TLR7-induced lupus","volume":"117","author":"Goel","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/art.v72.12","article-title":"Effects of gasdermin D in modulating murine lupus and its associated organ damage","volume":"72","author":"Wang","year":"2020","journal-title":"Arthritis Rheumatol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700905","article-title":"A high-throughput real-time imaging technique to quantify NETosis and distinguish mechanisms of cell death in human neutrophils","volume":"200","author":"Gupta","year":"2018","journal-title":"J Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3791\/66051","article-title":"Real-time high throughput technique to quantify neutrophil extracellular traps formation in human neutrophils","volume":"202","author":"Nakabo","year":"2023","journal-title":"J Vis Exp"},{"key":"B14","doi-asserted-by":"publisher","first-page":"14 41 1","DOI":"10.1002\/cpim.16","article-title":"Induction and quantification of NETosis","volume":"115","author":"Carmona-Rivera","year":"2016","journal-title":"Curr Protoc Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.134189","article-title":"Neutrophil dysregulation is pathogenic in idiopathic inflammatory myopathies","volume":"5","author":"Seto","year":"2020","journal-title":"JCI Insight"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.151005","article-title":"NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity","volume":"6","author":"Hiwa","year":"2021","journal-title":"JCI Insight"},{"key":"B17","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1186\/1471-2105-14-128","article-title":"Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool","volume":"14","author":"Chen","year":"2013","journal-title":"BMC Bioinf"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: a comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0736-z","article-title":"Single-cell transcriptome profiling reveals neutrophil heterogeneity in homeostasis and infection","volume":"21","author":"Xie","year":"2020","journal-title":"Nat Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.99276","article-title":"Neutrophil subsets and their gene signature associate with vascular inflammation and coronary atherosclerosis in lupus","volume":"3","author":"Carlucci","year":"2018","journal-title":"JCI Insight"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1908576116","article-title":"Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus","volume":"116","author":"Mistry","year":"2019","journal-title":"Proc Natl Acad Sci USA"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201746944","article-title":"Protocol for improved resolution of plasma cell subpopulations by flow cytometry","volume":"47","author":"Wilmore","year":"2017","journal-title":"Eur J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201746934","article-title":"A mouse model of systemic lupus erythematosus responds better to soluble TACI than to soluble BAFFR, correlating with depletion of plasma cells","volume":"47","author":"Haselmayer","year":"2017","journal-title":"Eur J Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03818-3","article-title":"APRIL limits atherosclerosis by binding to heparan sulfate proteoglycans","volume":"597","author":"Tsiantoulas","year":"2021","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-2553-8_11","article-title":"Quantification of neutrophils undergoing NET formation and distinguishing mechanisms of neutrophil cell death by use of a high-throughput method","volume":"2543","author":"Nakabo","year":"2022","journal-title":"Methods Mol Biol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0571-2","article-title":"Programmed 'disarming' of the neutrophil proteome reduces the magnitude of inflammation","volume":"21","author":"Adrover","year":"2020","journal-title":"Nat Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1515\/cclm-2012-0521","article-title":"Serum DNase I activity in systemic lupus erythematosus: correlation with immunoserological markers, the disease activity and organ involvement","volume":"51","author":"Skiljevic","year":"2013","journal-title":"Clin Chem Lab Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-332940","article-title":"Production of the plasma-cell survival factor a proliferation-inducing ligand (APRIL) peaks in myeloid precursor cells from human bone marrow","volume":"118","author":"Matthes","year":"2011","journal-title":"Blood"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3109\/07420528.2011.553017","article-title":"Methotrexate chronotherapy is effective against rheumatoid arthritis","volume":"28","author":"To","year":"2011","journal-title":"Chronobiol Int"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1177\/0748730410395527","article-title":"Altered expression of circadian clock genes in human chronic myeloid leukemia","volume":"26","author":"Yang","year":"2011","journal-title":"J Biol Rhythms"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1915773117","article-title":"Circadian control of interferon-sensitive gene expression in murine skin","volume":"117","author":"Greenberg","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B32","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.cell.2016.05.034","article-title":"Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity","volume":"166","author":"Sisirak","year":"2016","journal-title":"Cell"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2018.10.016","article-title":"The role of APRIL - A proliferation inducing ligand - In autoimmune diseases and expectations from its targeting","volume":"95","author":"Baert","year":"2018","journal-title":"J Autoimmun"},{"key":"B34","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1186\/s13075-015-0811-2","article-title":"Analyzing pathogenic (double-stranded (ds) DNA-specific) plasma cells via immunofluorescence microscopy","volume":"17","author":"Winter","year":"2015","journal-title":"Arthritis Res Ther"},{"key":"B35","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1128\/MCB.24.3.997-1006.2004","article-title":"APRIL-deficient mice have normal immune system development","volume":"24","author":"Varfolomeev","year":"2004","journal-title":"Mol Cell Biol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/art.33458","article-title":"Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice","volume":"64","author":"Jacob","year":"2012","journal-title":"Arthritis Rheum"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021012835","article-title":"The journey of neutropoiesis: how complex landscapes in bone marrow guide continuous neutrophil lineage determination","volume":"139","author":"Overbeeke","year":"2022","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3109\/07420528.2013.784773","article-title":"Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans","volume":"30","author":"Ackermann","year":"2013","journal-title":"Chronobiol Int"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1136\/ard-2022-223808","article-title":"Machine learning identifies clusters of longitudinal autoantibody profiles predictive of systemic lupus erythematosus disease outcomes","volume":"82","author":"Choi","year":"2023","journal-title":"Ann Rheum Dis"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2016-209519","article-title":"A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS)","volume":"76","author":"van Vollenhoven","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201601030R","article-title":"Myeloid Bmal1 deletion increases monocyte recruitment and worsens atherosclerosis","volume":"31","author":"Huo","year":"2017","journal-title":"FASEB J"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.314318","article-title":"Bmal1 deletion in myeloid cells attenuates atherosclerotic lesion development and restrains abdominal aortic aneurysm formation in hyperlipidemic mice","volume":"40","author":"Yang","year":"2020","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1901304","article-title":"Homeostatic milieu induces production of deoxyribonuclease 1-like 3 from myeloid cells","volume":"204","author":"Inokuchi","year":"2020","journal-title":"J Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2019097118","article-title":"Acute skin exposure to ultraviolet light triggers neutrophil-mediated kidney inflammation","volume":"118","author":"Skopelja-Gardner","year":"2021","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1465185\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:58:52Z","timestamp":1791194332000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1465185\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,27]]},"references-count":44,"alternative-id":["10.3389\/fimmu.2024.1465185"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1465185","relation":{"has-part":[{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2024.1465185.s001","asserted-by":"subject"},{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2024.1465185.s002","asserted-by":"subject"},{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2024.1465185.s003","asserted-by":"subject"},{"id-type":"doi","id":"https:\/\/doi.org\/10.3389\/fimmu.2024.1465185.s004","asserted-by":"subject"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,27]]},"article-number":"1465185"}}