{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:04:15Z","timestamp":1792605855522,"version":"4.5.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"},{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,11,25]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Differences in the ability of neutrophils to perform relevant effector functions has been identified in a variety of disease states. Although neutrophil functional heterogeneity is increasingly recognized during disease, few studies have examined neutrophil functional heterogeneity during periods of health. In this study, we systematically characterize neutrophil functional heterogeneity in a cohort of healthy human subjects using a range of biologically relevant agonists including immune complexes, bacterial ligands, and pathogens. With repeated testing over several years, we show that neutrophil functional capability represents a fixed phenotype for each individual. This neutrophil phenotype is preserved across a range of agonists and extends to a variety of effector functions including degranulation, neutrophil extracellular trap release, reactive oxygen species generation, phagocytosis, and bacterial killing. Using well-phenotyped healthy human subjects, we demonstrate that neutrophil functional heterogeneity is characterized by differences in neutrophil gene expression patterns. Altogether, our findings demonstrate that while neutrophil function is highly heterogeneous among healthy subjects, each individual's functional capability represents a fixed phenotype defined by a distinct neutrophil gene expression profile. These findings may be relevant during disease states where the ability to perform relevant neutrophil effector functions may impact disease course and\/or clinical outcome.<\/jats:p>","DOI":"10.1002\/jlb.4a0322-164r","type":"journal-article","created":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T08:10:59Z","timestamp":1659427859000},"page":"1485-1495","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Neutrophil functional heterogeneity is a fixed phenotype and is associated with distinct gene expression profiles"],"prefix":"10.1093","volume":"112","author":[{"given":"Stacey A","family":"Maskarinec","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases and Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"McKelvy","sequence":"additional","affiliation":[{"name":"Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"Boyle","sequence":"additional","affiliation":[{"name":"Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Halie","family":"Hotchkiss","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madelaine E","family":"Duarte","sequence":"additional","affiliation":[{"name":"Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bechtler","family":"Addison","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases and Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Amato","sequence":"additional","affiliation":[{"name":"Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Khandelwal","sequence":"additional","affiliation":[{"name":"Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gowthami M","family":"Arepally","sequence":"additional","affiliation":[{"name":"Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace M","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Hematology, Duke University Medical Center , Durham, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,2]]},"reference":[{"key":"2023032107470885200_","article-title":"Two new neutrophil subsets define a discriminating sepsis signature","volume-title":"Am J Respir Crit Care Med","author":"Meghraoui-Kheddar","year":"2021"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"L1102","DOI":"10.1152\/ajplung.00380.2014","article-title":"Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS","volume":"308","author":"Kangelaris","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0162490","article-title":"Extremes of interferon-stimulated gene expression associate with worse outcomes in the acute respiratory distress syndrome","volume":"11","author":"Nick","year":"2016","journal-title":"PLoS One"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","DOI":"10.1084\/jem.20210582","article-title":"Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19","volume":"218","author":"Wilk","year":"2021","journal-title":"J Exp Med"},{"key":"2023032107470885200_","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":"Schulte-Schrepping","year":"2020","journal-title":"Cell"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1182\/bloodadvances.2019000235","article-title":"Heterogeneity in neutrophil responses to immune complexes","volume":"3","author":"Duarte","year":"2019","journal-title":"Blood Adv"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1182\/blood-2005-12-4997","article-title":"Neutrophil responsiveness to IgG, as determined by fixed ratios of mRNA levels for activating and inhibitory FcgammaRII (CD32), is stable over time and unaffected by cytokines","volume":"108","author":"van Mirre","year":"2006","journal-title":"Blood"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1182\/blood.V95.5.1533.005k01_1533_1540","article-title":"Characterization of a murine monoclonal antibody that mimics heparin-induced thrombocytopenia antibodies","volume":"95","author":"Arepally","year":"2000","journal-title":"Blood"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"5021","DOI":"10.1182\/blood-2010-03-276964","article-title":"Monocyte-bound PF4 in the pathogenesis of heparin-induced thrombocytopenia","volume":"116","author":"Rauova","year":"2010","journal-title":"Blood"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-62703-845-4","volume-title":"Neutrophil methods and protocols","author":"Quinn","year":"2014","edition":"2nd"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.1161\/ATVBAHA.113.301627","article-title":"Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state","volume":"33","author":"Borissoff","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1038\/s41467-019-09160-7","article-title":"Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia","volume":"10","author":"Perdomo","year":"2019","journal-title":"Nat Commun"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"e286","DOI":"10.1097\/PCC.0000000000001496","article-title":"Neutrophil extracellular traps in children with meningococcal sepsis","volume":"19","author":"Hoppenbrouwers","year":"2018","journal-title":"Pediatr Crit Care Med"},{"key":"2023032107470885200_"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","article-title":"HTSeq\u2013a Python framework to work with high-throughput sequencing data","volume":"31","author":"Anders","year":"2015","journal-title":"Bioinformatics"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nmeth.3252","article-title":"Orchestrating high-throughput genomic analysis with bioconductor","volume":"12","author":"Huber","year":"2015","journal-title":"Nat Methods"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1126\/science.6310757","article-title":"Is cytosolic ionized calcium regulating neutrophil activation?","volume":"221","author":"Pozzan","year":"1983","journal-title":"Science"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","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":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"2689","DOI":"10.4049\/jimmunol.1201719","article-title":"Neutrophil extracellular traps: double-edged swords of innate immunity","volume":"189","author":"Kaplan","year":"2012","journal-title":"J Immunol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2014.00467","article-title":"Neutrophil-mediated phagocytosis of Staphylococcus aureus","volume":"5","author":"van Kessel","year":"2014","journal-title":"Front Immunol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.650808","article-title":"The inhibitory receptor CLEC12A regulates PI3K-Akt signaling to inhibit neutrophil activation and cytokine release","volume":"12","author":"Pare","year":"2021","journal-title":"Front Immunol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"29501","DOI":"10.1074\/jbc.M513471200","article-title":"Phospholipase C epsilon suppresses integrin activation","volume":"281","author":"Lad","year":"2006","journal-title":"J Biol Chem"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1038\/s41467-021-22548-8","article-title":"Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease","volume":"12","author":"Watt","year":"2021","journal-title":"Nat Commun"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/jlb.40.2.133","article-title":"Gender-related variations and interaction of human neutrophil cyclooxygenase and oxidative burst metabolites","volume":"40","author":"Mallery","year":"1986","journal-title":"J Leukoc Biol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/s41590-018-0049-7","article-title":"Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors","volume":"19","author":"Patin","year":"2018","journal-title":"Nat Immunol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"538","DOI":"10.4049\/jimmunol.1100450","article-title":"Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus","volume":"187","author":"Villanueva","year":"2011","journal-title":"J Immunol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.jdermsci.2018.08.010","article-title":"Neutrophils contribute to vasculitis by increased release of neutrophil extracellular traps in Behcet's disease","volume":"92","author":"Safi","year":"2018","journal-title":"J Dermatol Sci"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/nrneph.2016.71","article-title":"The role of neutrophils and NETosis in autoimmune and renal diseases","volume":"12","author":"Gupta","year":"2016","journal-title":"Nat Rev Nephrol"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"R84","DOI":"10.1186\/ar4264","article-title":"Degradation of neutrophil extracellular traps co-varies with disease activity in patients with systemic lupus erythematosus","volume":"15","author":"Leffler","year":"2013","journal-title":"Arthritis Res Ther"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1097\/SHK.0b013e318173ef9c","article-title":"Immature circulating neutrophils in sepsis have impaired phagocytosis and calcium signaling","volume":"30","author":"Taneja","year":"2008","journal-title":"Shock"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1182\/bloodadvances.2020003568","article-title":"A neutrophil activation signature predicts critical illness and mortality in COVID-19","volume":"5","author":"Meizlish","year":"2021","journal-title":"Blood Adv"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2014.00448","article-title":"Granule protein processing and regulated secretion in neutrophils","volume":"5","author":"Sheshachalam","year":"2014","journal-title":"Front Immunol"},{"key":"2023032107470885200_","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":"2023032107470885200_","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-021-90631-7","article-title":"Expression of the myeloid inhibitory receptor CLEC12A correlates with disease activity and cytokines in early rheumatoid arthritis","volume":"11","author":"Vaillancourt","year":"2021","journal-title":"Sci Rep"},{"key":"2023032107470885200_","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2017.01498","article-title":"Neutrophil functional heterogeneity: identification of competitive phagocytosis","volume":"8","author":"Hellebrekers","year":"2017","journal-title":"Front Immunol"}],"container-title":["Journal of Leukocyte Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/JLB.4A0322-164R","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/JLB.4A0322-164R","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/112\/6\/1485\/49470460\/jlb11205.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jleukbio\/article-pdf\/112\/6\/1485\/49470460\/jlb11205.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T06:58:24Z","timestamp":1700895504000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jleukbio\/article\/112\/6\/1485\/6976243"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,2]]},"references-count":37,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,8,2]]},"published-print":{"date-parts":[[2022,11,25]]}},"URL":"https:\/\/doi.org\/10.1002\/jlb.4a0322-164r","relation":{},"ISSN":["0741-5400","1938-3673"],"issn-type":[{"value":"0741-5400","type":"print"},{"value":"1938-3673","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12]]},"published":{"date-parts":[[2022,8,2]]},"assertion":[{"value":"2022-03-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-07-18","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-08-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}