{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T16:11:09Z","timestamp":1782576669603,"version":"3.54.5"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T00:00:00Z","timestamp":1641340800000},"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>Neutrophil extracellular traps NETs have been linked to glucose and the pathogenesis of type 1 diabetes mellitus (T1DM). NETs also play a role in vascular inflammation and the development of coronary artery disease (CAD). The role of NETs in CAD progression in patients with long-term T1DM is unclear. We aimed to 1) investigate whether levels of circulating NETs markers were elevated in long-term T1DM subjects compared to controls, and 2) explore whether levels of NETs were related to the presence of CAD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Material and Methods<\/jats:title><jats:p>102 patients with &amp;gt; 45 years of T1DM and 75 age-matched controls were enrolled in a cross-sectional study. Median age was 62 years. Computed tomography coronary angiography (CTCA) was performed in 148 subjects without established coronary heart disease. For the current study, CAD was defined as a coronary artery stenosis &amp;gt;50%. Double-stranded deoxyribonucleic acid (dsDNA) was measured by a nucleic acid stain, myeloperoxidase-DNA (MPO-DNA), citrullinated histone 3 (H3Cit) and peptidylarginine deiminase 4 (PAD4) by ELISAs, while gene expression of PAD4 was measured in leukocytes from PAXgene tubes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Circulating MPO-DNA levels were significantly lower in patients with T1DM than in controls (0.17 vs 0.29 OD, p&amp;lt;0.001), while dsDNA, H3Cit, PAD4 and gene expression of PAD4 did not differ with respect to the presence of T1DM. There were no significant associations between NETs markers and HbA1c in the T1DM group. None of the NETs markers differed according to the presence of CAD in patients with T1DM. While all circulating NETs markers correlated significantly with circulating neutrophils in the control group (r=0.292-393, p&amp;lt;0.014), only H3Cit and PAD4 correlated with neutrophils in the T1DM group (r= 0.330-0.449, p \u2264 0.001).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In this cross-sectional study of patients with long-term T1DM and age-matched controls, circulating NETs levels were not consistently associated with the presence of T1DM or glycemic status, and did not differ according to the presence of CAD in patients with T1DM. Our results entail the possibility of altered neutrophil function and reduced NETosis in T1DM. This warrants further investigation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.799539","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T11:43:37Z","timestamp":1641383017000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["NETosis in Long-Term Type 1 Diabetes Mellitus and Its Link to Coronary Artery Disease"],"prefix":"10.3389","volume":"12","author":[{"given":"Sverre Gr\u00f8ver","family":"Aukrust","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine Bech","family":"Holte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trine B.","family":"Opstad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingebj\u00f8rg","family":"Seljeflot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tore Julsrud","family":"Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnhild","family":"Helseth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092385","article-title":"Neutrophil Extracellular Traps Kill Bacteria","volume":"303","author":"Brinkmann","year":"2004","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2921","article-title":"Neutrophils at Work","volume":"15","author":"Nauseef","year":"2014","journal-title":"Nat Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1134\/S0006297920100065","article-title":"NETosis: Molecular Mechanisms, Role in Physiology and Pathology","volume":"85","author":"Vorobjeva","year":"2020","journal-title":"Biochem (Mosc)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00360","article-title":"Activation of PAD4 in NET Formation","volume":"3","author":"Rohrbach","year":"2012","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12437","article-title":"Metabolic Requirements for Neutrophil Extracellular Traps Formation","volume":"145","author":"Rodriguez-Espinosa","year":"2015","journal-title":"Immunology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1186\/s12872-019-1205-1","article-title":"Glucose Associated NETosis in Patients With ST-Elevation Myocardial Infarction: An Observational Study","volume":"19","author":"Helseth","year":"2019","journal-title":"BMC Cardiovasc Disord"},{"key":"B7","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s00592-014-0676-x","article-title":"NETosis is Induced by High Glucose and Associated With Type 2 Diabetes","volume":"52","author":"Menegazzo","year":"2015","journal-title":"Acta Diabetol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1159\/000444881","article-title":"Circulating Neutrophil Extracellular Trap Levels in Well-Controlled Type 2 Diabetes and Pathway Involved in Their Formation Induced by High-Dose Glucose","volume":"83","author":"Miyoshi","year":"2016","journal-title":"Pathobiology"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2337\/db12-1345","article-title":"Reduction of Circulating Neutrophils Precedes and Accompanies Type 1 Diabetes","volume":"62","author":"Valle","year":"2013","journal-title":"Diabetes"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1530\/JME-20-0128","article-title":"NETosis Contributes to the Pathogenesis of Diabetes and its Complications","volume":"65","author":"Njeim","year":"2020","journal-title":"J Mol Endocrinol"},{"key":"B11","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1097\/MOH.0000000000000008","article-title":"Neutrophils and Type 1 Autoimmune Diabetes","volume":"21","author":"Battaglia","year":"2014","journal-title":"Curr Opin Hematol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2337\/db14-0480","article-title":"Increased Neutrophil Elastase and Proteinase 3 and Augmented NETosis are Closely Associated With \u03b2-Cell Autoimmunity in Patients With Type 1 Diabetes","volume":"63","author":"Wang","year":"2014","journal-title":"Diabetes"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00661","article-title":"Neutrophil Extracellular Trap Induced Dendritic Cell Activation Leads to Th1 Polarization in Type 1 Diabetes","volume":"11","author":"Parackova","year":"2020","journal-title":"Front Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.2337\/db14-1382","article-title":"Autoimmune Diabetes: Caught in a NET","volume":"63","author":"Leslie","year":"2014","journal-title":"Diabetes"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.105","article-title":"Neutrophil Extracellular Traps in Immunity and Disease","volume":"18","author":"Papayannopoulos","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.119.312463","article-title":"Neutrophil Extracellular Traps: Villains and Targets in Arterial, Venous, and Cancer-Associated Thrombosis","volume":"39","author":"Th\u00e5lin","year":"2019","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309692","article-title":"Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis","volume":"120","author":"D\u00f6ring","year":"2017","journal-title":"Circ Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.315931","article-title":"Neutrophil Extracellular Traps Participate in Cardiovascular Diseases: Recent Experimental and Clinical Insights","volume":"126","author":"D\u00f6ring","year":"2020","journal-title":"Circ Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00928","article-title":"Neutrophil Extracellular Traps and Endothelial Dysfunction in Atherosclerosis and Thrombosis","volume":"8","author":"Qi","year":"2017","journal-title":"Front Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1177\/2047487318760618","article-title":"Markers of Neutrophil Extracellular Traps are Associated With Adverse Clinical Outcome in Stable Coronary Artery Disease","volume":"25","author":"Langseth","year":"2018","journal-title":"Eur J Prev Cardiol"},{"key":"B21","doi-asserted-by":"publisher","first-page":"5007","DOI":"10.1038\/s41598-020-61971-7","article-title":"Double-Stranded DNA and NETs Components in Relation to Clinical Outcome After ST-Elevation Myocardial Infarction","volume":"10","author":"Langseth","year":"2020","journal-title":"Sci Rep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"7816491","DOI":"10.1155\/2019\/7816491","article-title":"Neutrophil Extracellular Trap Components Associate With Infarct Size, Ventricular Function, and Clinical Outcome in STEMI","author":"Helseth","year":"2019","journal-title":"Mediators Inflamm 2019"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.2337\/dc06-1161","article-title":"Type 1 Diabetes and Coronary Artery Disease","volume":"29","author":"Orchard","year":"2006","journal-title":"Diabetes Care"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2337\/dc14-1720","article-title":"Type 1 Diabetes Mellitus and Cardiovascular Disease: A Scientific Statement From the American Heart Association and American Diabetes Association","volume":"37","author":"de Ferranti","year":"2014","journal-title":"Diabetes Care"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2017.06.007","article-title":"Hand, Shoulder and Back Stiffness in Long-Term Type 1 Diabetes; Cross-Sectional Association With Skin Collagen Advanced Glycation End-Products. The Dialong Study","volume":"31","author":"Holte","year":"2017","journal-title":"J Diabetes Complications"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdiacomp.2019.01.006","article-title":"Undiagnosed Coronary Artery Disease in Long-Term Type 1 Diabetes. The Dialong Study","volume":"33","author":"Holte","year":"2019","journal-title":"J Diabetes Complications"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/nm.1959","article-title":"Netting Neutrophils in Autoimmune Small-Vessel Vasculitis","volume":"15","author":"Kessenbrock","year":"2009","journal-title":"Nat Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2018.05.027","article-title":"Coronary Calcium Score and Cardiovascular Risk","volume":"72","author":"Greenland","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e0218946","DOI":"10.1371\/journal.pone.0218946","article-title":"Neutrophil Extracellular Traps (NET) Induced by Different Stimuli: A Comparative Proteomic Analysis","volume":"14","author":"Petretto","year":"2019","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.678771","article-title":"A Bittersweet Response to Infection in Diabetes; Targeting Neutrophils to Modify Inflammation and Improve Host Immunity","volume":"12","author":"Dowey","year":"2021","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0000000000000485","article-title":"Neutrophils and Type 1 Diabetes: Current Knowledge and Suggested Future Directions","volume":"26","author":"Battaglia","year":"2019","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.12469","article-title":"Neutrophils in Type 1 Diabetes","volume":"7","author":"Huang","year":"2016","journal-title":"J Diabetes Invest"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1590\/S0100-879X2006005000143","article-title":"Neutrophil Function and Metabolism in Individuals With Diabetes Mellitus","volume":"40","author":"Alba-Loureiro","year":"2007","journal-title":"Braz J Med Biol Res"},{"key":"B34","first-page":"1","article-title":"Neutrophil Function Impairment Is a Host Susceptibility Factor to Bacterial Infection in Diabetes","volume-title":"Cells Immune Syst","author":"Insuela","year":"2019"},{"key":"B35","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.cca.2016.05.029","article-title":"NETosis Markers: Quest for Specific, Objective, and Quantitative Markers","volume":"459","author":"Masuda","year":"2016","journal-title":"Clin Chim Acta"},{"key":"B36","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1007\/s12016-020-08804-7","article-title":"A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics","volume":"61","author":"Mutua","year":"2021","journal-title":"Clin Rev Allergy Immunol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.3390\/ijms21041391","article-title":"P2Y(12) Inhibition Beyond Thrombosis: Effects on Inflammation","volume":"21","author":"Mansour","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2010.10.005","article-title":"Statins Enhance Formation of Phagocyte Extracellular Traps","volume":"8","author":"Chow","year":"2010","journal-title":"Cell Host Microbe"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.799539\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T11:43:42Z","timestamp":1641383022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.799539\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,5]]},"references-count":38,"alternative-id":["10.3389\/fimmu.2021.799539"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.799539","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,5]]},"article-number":"799539"}}