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Evidence of neutrophil dysfunction in COVID-19 is based on transcriptomics or single functional assays. Cell functions are interwoven pathways, and understanding the effect across the spectrum of neutrophil function may identify therapeutic targets. Objectives: Examine neutrophil phenotype and function in 41 hospitalised, non-ICU COVID-19 patients versus 23 age-matched controls (AMC) and 26 community acquired pneumonia patients (CAP). Methods: Isolated neutrophils underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NETosis and receptor expression. Circulating DNAse 1 activity, levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI were measured and correlated to clinical outcome. Serial sampling on day three to five post hospitalization were also measured. The effect of ex vivo PI3K inhibition was measured in a further cohort of 18 COVID-19 patients. Results: Compared to AMC and CAP, COVID-19 neutrophils demonstrated elevated transmigration (p = 0.0397) and NETosis (p = 0.0332), and impaired phagocytosis (p = 0.0036) associated with impaired ROS generation (p &lt; 0.0001). The percentage of CD54+ neutrophils (p &lt; 0.001) was significantly increased, while surface expression of CD11b (p = 0.0014) and PD-L1 (p = 0.006) were significantly decreased in COVID-19. COVID-19 and CAP patients showed increased systemic markers of NETosis including increased cfDNA (p = 0.0396) and impaired DNAse activity (p &lt; 0.0001). The ex vivo inhibition of PI3K \u03b3 and \u03b4 reduced NET release by COVID-19 neutrophils (p = 0.0129). Conclusions: COVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration and NETosis, and impaired antimicrobial responses. These changes highlight that targeting neutrophil function may help modulate COVID-19 severity.<\/jats:p>","DOI":"10.3390\/cells11182901","type":"journal-article","created":{"date-parts":[[2022,9,18]],"date-time":"2022-09-18T22:12:43Z","timestamp":1663539163000},"page":"2901","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Dysregulated Neutrophil Phenotype and Function in Hospitalised Non-ICU COVID-19 Pneumonia"],"prefix":"10.3390","volume":"11","author":[{"given":"Kylie B. R.","family":"Belchamber","sequence":"first","affiliation":[{"name":"Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0524-9449","authenticated-orcid":false,"given":"Onn S.","family":"Thein","sequence":"additional","affiliation":[{"name":"Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Hazeldine","sequence":"additional","affiliation":[{"name":"National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre, Queen Elizabeth Hospital Birmingham, Birmingham B15 2TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances S.","family":"Grudzinska","sequence":"additional","affiliation":[{"name":"Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1670-1680","authenticated-orcid":false,"given":"Aduragbemi A.","family":"Faniyi","sequence":"additional","affiliation":[{"name":"Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5793-415X","authenticated-orcid":false,"given":"Michael J.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9294-1200","authenticated-orcid":false,"given":"Alice 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Edgbaston, Birmingham B12 2GW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Thickett","sequence":"additional","affiliation":[{"name":"Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9325-5026","authenticated-orcid":false,"given":"Aaron","family":"Scott","sequence":"additional","affiliation":[{"name":"Birmingham Acute Care Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,16]]},"reference":[{"key":"ref_1","first-page":"157","article-title":"WHO Declares COVID-19 a Pandemic","volume":"91","author":"Cucinotta","year":"2020","journal-title":"Acta Biomed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1172\/JCI12568","article-title":"Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis","volume":"107","author":"Kolb","year":"2001","journal-title":"J. Clin. Invest."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1164\/rccm.202008-3265OC","article-title":"Tissue-Specific Immunopathology in Fatal COVID-19","volume":"203","author":"Dorward","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1189\/jlb.4VMR1114-555R","article-title":"Neutrophils in viral infections: Current concepts and caveats","volume":"98","author":"Galani","year":"2015","journal-title":"J. Leukoc. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1007\/s00441-017-2748-z","article-title":"Neutrophils in the lung: \u201cThe first responders\u201d","volume":"371","author":"Aulakh","year":"2017","journal-title":"Cell Tissue Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104364","DOI":"10.1016\/j.jcv.2020.104364","article-title":"Clinical features and short-term outcomes of 221 patients with COVID-19 in Wuhan, China","volume":"127","author":"Zhang","year":"2020","journal-title":"J. Clin. Virol."},{"key":"ref_7","first-page":"497","article-title":"Poor COVID-19 outcomes and deaths linked to advanced age and pre-existing conditions","volume":"127","author":"Printz","year":"2021","journal-title":"Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101205","DOI":"10.1016\/j.arr.2020.101205","article-title":"Aging in COVID-19: Vulnerability, immunity and intervention","volume":"65","author":"Chen","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1182\/blood-2013-08-519520","article-title":"Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: Toward targeted treatments for immunosenescence","volume":"123","author":"Sapey","year":"2014","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1189\/jlb.70.6.881","article-title":"Senescence in innate immune responses: Reduced neutrophil phagocytic capacity and CD16 expression in elderly humans","volume":"70","author":"Butcher","year":"2001","journal-title":"J. Leukoc. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1111\/acel.12222","article-title":"Impaired neutrophil extracellular trap formation: A novel defect in the innate immune system of aged individuals","volume":"13","author":"Hazeldine","year":"2014","journal-title":"Aging Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1136\/thoraxjnl-2018-212826","article-title":"Neutrophils in community-acquired pneumonia: Parallels in dysfunction at the extremes of age","volume":"75","author":"Grudzinska","year":"2020","journal-title":"Thorax"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4065362","DOI":"10.1155\/2018\/4065362","article-title":"Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality","volume":"2018","author":"Patel","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1164\/rccm.201509-1818OC","article-title":"Acute Respiratory Distress Syndrome Neutrophils Have a Distinct Phenotype and Are Resistant to Phosphoinositide 3-Kinase Inhibition","volume":"194","author":"Juss","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1325","DOI":"10.1164\/rccm.201704-0814OC","article-title":"Pulmonary infections in the elderly lead to impaired neutrophil targetting, which is improved by simvastatin","volume":"196","author":"Sapey","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/nri1839","article-title":"Statin therapy and autoimmune disease: From protein prenylation to immunomodulation","volume":"6","author":"Greenwood","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1164\/rccm.201812-2328OC","article-title":"Simvastatin Improves Neutrophil Function and Clinical Outcomes in Pneumonia. A pilot randomized controlled clinical trial","volume":"200","author":"Sapey","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.exger.2017.12.020","article-title":"Inflammation and neutrophil immunosenescence in health and disease: Targeted treatments to improve clinical outcomes in the elderly","volume":"105","author":"Drew","year":"2018","journal-title":"Exp. Gerontol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3389\/fphys.2018.00113","article-title":"Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types?","volume":"9","author":"Rosales","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2063","DOI":"10.3389\/fimmu.2020.02063","article-title":"Excessive Neutrophils and Neutrophil Extracellular Traps in COVID-19","volume":"11","author":"Wang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13073-020-00823-5","article-title":"Disease severity-specific neutrophil signatures in blood transcriptomes stratify COVID-19 patients","volume":"13","author":"Aschenbrenner","year":"2021","journal-title":"Genome Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1016\/j.cell.2020.08.001","article-title":"Severe COVID-19 Is Marked by a Dysregulated Myeloid Cell Compartment","volume":"182","author":"Reusch","year":"2020","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1182\/blood.2020007008","article-title":"Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome","volume":"136","author":"Middleton","year":"2020","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6151","DOI":"10.1172\/JCI141374","article-title":"Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis","volume":"130","author":"Skendros","year":"2020","journal-title":"J. Clin. Invest."},{"key":"ref_25","first-page":"e138999","article-title":"Neutrophil extracellular traps in COVID-19","volume":"5","author":"Zuo","year":"2020","journal-title":"JCI Insight"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19630","DOI":"10.1038\/s41598-020-76781-0","article-title":"The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19)","volume":"10","author":"Arcanjo","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102925","DOI":"10.1016\/j.ebiom.2020.102925","article-title":"Vascular occlusion by neutrophil extracellular traps in COVID-19","volume":"58","author":"Leppkes","year":"2020","journal-title":"EBioMedicine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"680134","DOI":"10.3389\/fimmu.2021.680134","article-title":"Neutrophils and COVID-19: Active Participants and Rational Therapeutic Targets","volume":"12","author":"Hazeldine","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e000644","DOI":"10.1136\/bmjresp-2020-000644","article-title":"Ethnicity and risk of death in patients hospitalised for COVID-19 infection in the UK: An observational cohort study in an urban catchment area","volume":"7","author":"Sapey","year":"2020","journal-title":"BMJ Open Respir. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"m3339","DOI":"10.1136\/bmj.m3339","article-title":"Risk stratification of patients admitted to hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: Development and validation of the 4C Mortality Score","volume":"370","author":"Knight","year":"2020","journal-title":"BMJ"},{"key":"ref_31","unstructured":"National Institute for Health and Care Excellence (2021). COVID-19 Rapid Guideline: Managing COVID-19."},{"key":"ref_32","first-page":"2526","article-title":"Acute respiratory distress syndrome: The Berlin Definition","volume":"307","author":"Force","year":"2012","journal-title":"JAMA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"R25","DOI":"10.1186\/ar3707","article-title":"Specific post-translational histone modifications of neutrophil extracellular traps as immunogens and potential targets of lupus autoantibodies","volume":"14","author":"Liu","year":"2012","journal-title":"Arthritis Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/S2213-2600(19)30369-8","article-title":"Development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: A secondary analysis of randomised controlled trials","volume":"8","author":"Sinha","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Injarabian, L., Devin, A., Ransac, S., and Marteyn, B.S. (2019). Neutrophil Metabolic Shift during their Lifecycle: Impact on their Survival and Activation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010287"},{"key":"ref_36","first-page":"479","article-title":"Increased peripheral blood neutrophil activation phenotypes and NETosis in critically ill COVID-19 patients: A case series and review of the literature","volume":"74","author":"Moshensky","year":"2021","journal-title":"Clin. Infect. Dis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"685","DOI":"10.3389\/fimmu.2019.00685","article-title":"Traumatic Injury and Exposure to Mitochondrial-Derived Damage Associated Molecular Patterns Suppresses Neutrophil Extracellular Trap Formation","volume":"10","author":"Hazeldine","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_38","first-page":"1178","article-title":"NETosis: Molecular Mechanisms, Role in Physiology and Pathology","volume":"85","author":"Vorobjeva","year":"2020","journal-title":"Biochemistry"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1097\/TA.0000000000001919","article-title":"Reduced deoxyribonuclease enzyme activity in response to high postinjury mitochondrial DNA concentration provides a therapeutic target for Systemic Inflammatory Response Syndrome","volume":"85","author":"McIlroy","year":"2018","journal-title":"J. Trauma Acute Care Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s41479-021-00083-w","article-title":"The role of co-infections and secondary infections in patients with COVID-19","volume":"13","author":"Feldman","year":"2021","journal-title":"Pneumonia"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Buehler, P.K., Zinkernagel, A.S., Hofmaenner, D.A., Garc\u00eda, P.D.W., Acevedo, C.T., G\u00f3mez-Mejia, A., Shambat, S.M., Andreoni, F., Maibach, M.A., and Bartussek, J. (2020). Bacterial pulmonary superinfections are associated with unfavourable outcomes in critically ill COVID-19 patients. medRxiv.","DOI":"10.1101\/2020.09.10.20191882"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"198005","DOI":"10.1016\/j.virusres.2020.198005","article-title":"Co-infection with respiratory pathogens among COVID-2019 cases","volume":"285","author":"Zhu","year":"2020","journal-title":"Virus Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"373","DOI":"10.3389\/fcimb.2017.00373","article-title":"Neutrophils to the ROScue: Mechanisms of NADPH Oxidase Activation and Bacterial Resistance","volume":"7","author":"Nguyen","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e20201129","DOI":"10.1084\/jem.20201129","article-title":"SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology","volume":"217","author":"Veras","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1701389","DOI":"10.1183\/13993003.01389-2017","article-title":"Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: Secondary analysis of a randomised controlled trial","volume":"51","author":"Ebrahimi","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1159\/000521594","article-title":"Impaired Degradation of Neutrophil Extracellular Traps: A Possible Severity Factor of Elderly Male COVID-19 Patients","volume":"14","author":"Parplys","year":"2022","journal-title":"J. Innate Immun."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cels.2020.05.012","article-title":"Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection","volume":"11","author":"Messner","year":"2020","journal-title":"Cell Syst."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.cels.2020.10.003","article-title":"Large-Scale Multi-omic Analysis of COVID-19 Severity","volume":"12","author":"Overmyer","year":"2021","journal-title":"Cell Syst."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.cell.2020.05.032","article-title":"Proteomic and Metabolomic Characterization of COVID-19 Patient Sera","volume":"182","author":"Shen","year":"2020","journal-title":"Cell"},{"key":"ref_50","first-page":"e157342","article-title":"Disulfiram inhibits neutrophil extraelular trap formation protecting rodents from acute lung injury and SARS-CoV2 infection","volume":"7","author":"Adrover","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/ncb1536","article-title":"Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions","volume":"9","author":"Andrew","year":"2007","journal-title":"Nat. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1016\/j.micinf.2003.09.014","article-title":"Phagocytosis by neutrophils","volume":"5","author":"Lee","year":"2003","journal-title":"Microbes Infect."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0955-0674(02)00311-3","article-title":"Roles of PI3Ks in leukocyte chemotaxis and phagocytosis","volume":"14","author":"Stephens","year":"2002","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"134","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":"ref_55","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.3389\/fimmu.2019.02320","article-title":"Effect of Adhesion and Substrate Elasticity on Neutrophil Extracellular Trap Formation","volume":"10","author":"Erpenbeck","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1189\/jlb.4A0615-261RR","article-title":"Neutrophil extracellular traps release induced by Leishmania: Role of PI3K\u03b3, ERK, PI3K\u03c3, PKC, and [Ca2+]","volume":"100","author":"Rochael","year":"2016","journal-title":"J. Leukoc. Biol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.3389\/fimmu.2020.02094","article-title":"PI3K\u03b4 Inhibition as a Potential Therapeutic Target in COVID-19","volume":"11","author":"Palma","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1111\/cei.12679","article-title":"Expression of CD11c and EMR2 on neutrophils: Potential diagnostic biomarkers for sepsis and systemic inflammation","volume":"182","author":"Lewis","year":"2015","journal-title":"Clin. Exp. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1182\/blood-2016-04-713206","article-title":"Mature CD10(+) and immature CD10(\u2212) neutrophils present in G-CSF-treated donors display opposite effects on T cells","volume":"129","author":"Marini","year":"2017","journal-title":"Blood"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/S1074-7613(03)00263-2","article-title":"Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence","volume":"19","author":"Martin","year":"2003","journal-title":"Immunity"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1038\/s41591-020-0944-y","article-title":"A single-cell atlas of the peripheral immune response in patients with severe COVID-19","volume":"26","author":"Wilk","year":"2020","journal-title":"Nat. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1189\/jlb.0905496","article-title":"Identification of a phenotypically and functionally distinct population of long-lived neutrophils in a model of reverse endothelial migration","volume":"79","author":"Buckley","year":"2006","journal-title":"J. Leukoc. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e1271","DOI":"10.1002\/cti2.1271","article-title":"Kinetics of peripheral blood neutrophils in severe coronavirus disease 2019","volume":"10","author":"Metzemaekers","year":"2021","journal-title":"Clin. Transl. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1038\/s41586-020-2600-6","article-title":"Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis","volume":"588","author":"Carvelli","year":"2020","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Shambat, S.M., G\u00f3mez-Mejia, A., Schweizer, T.A., Huemer, M., Chang, C.C., Acevedo, C., Pijuan, J.B., Vulin, C., Miroshnikova, N., and Hofm\u00e4nner, D.A. (2020). Neutrophil and monocyte dysfunctional effector response towards bacterial challenge in critically-ill COVID-19 patients. bioRxiv.","DOI":"10.1101\/2020.12.01.406306"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.cell.2020.04.026","article-title":"Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19","volume":"181","author":"Liu","year":"2020","journal-title":"Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"eabg9873","DOI":"10.1126\/sciimmunol.abg9873","article-title":"Inflammatory profiles across the spectrum of disease reveal a distinct role for GM-CSF in severe COVID-19","volume":"6","author":"Thwaites","year":"2021","journal-title":"Sci. Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1007\/s11239-020-02324-z","article-title":"Neutrophil extracellular traps and thrombosis in COVID-19","volume":"51","author":"Zuo","year":"2021","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s13054-022-04002-3","article-title":"Impairment of neutrophil functions and homeostasis in COVID-19 patients: Association with disease severity","volume":"26","author":"Loyer","year":"2022","journal-title":"Crit. Care"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e1128","DOI":"10.1097\/CCM.0000000000003405","article-title":"Vitamin D to Prevent Lung Injury Following Esophagectomy-A Randomized, Placebo-Controlled Trial","volume":"46","author":"Parekh","year":"2018","journal-title":"Crit Care Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1086\/323084","article-title":"Immune-mediated phagocytosis and killing of Streptococcus pneumoniae are associated with direct and bystander macrophage apoptosis","volume":"184","author":"Dockrell","year":"2001","journal-title":"J. Infect. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Bewley, M.A., Belchamber, K.B.R., Chana, K.K., Budd, R.C., Donaldson, G., Wedzicha, J.A., Brightling, C.E., Kilty, I., Donnelly, L.E., and Barnes, P.J. (2016). Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163139"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0014-2999(03)02153-8","article-title":"Inhibitory capacity of different steroids on neutrophil migration across a bilayer of endothelial and bronchial epithelial cells","volume":"477","author":"Demkow","year":"2003","journal-title":"Eur. J. Pharmacol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1203\/00006450-199910000-00008","article-title":"Mechanism for dexamethasone inhibition of neutrophil migration upon exposure to lipopolysaccharide in vitro: Role of neutrophil interleukin-8 release","volume":"46","author":"Zentay","year":"1999","journal-title":"Pediatric Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/S0002-9394(14)70131-X","article-title":"Peribulbar corticosteroid injection: Vitreal and serum concentrations after dexamethasone disodium phosphate injection","volume":"123","author":"Weijtens","year":"1997","journal-title":"Am. J. Ophthalmol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/18\/2901\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:33:08Z","timestamp":1760142788000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/18\/2901"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,16]]},"references-count":75,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["cells11182901"],"URL":"https:\/\/doi.org\/10.3390\/cells11182901","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.06.08.21258535","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,16]]}}}