title: A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs.
abstract: Neutrophil-specific genes are abundant in PBMC microarrays from lupus patients because of the presence of low-density granulocytes (LDGs) in mononuclear cell fractions. The functionality and pathogenicity of these LDGs have not been characterized. We developed a technique to purify LDGs from lupus PBMCs and assessed their phenotype, function, and potential role in disease pathogenesis. LDGs, their autologous lupus neutrophils, and healthy control neutrophils were compared with regard to their microbicidal and phagocytic capacities, generation of reactive oxygen species, activation status, inflammatory cytokine profile, and type I IFN expression and signatures. The capacity of LDGs to kill endothelial cells and their antiangiogenic potential were also assessed. LDGs display an activated phenotype, secrete increased levels of type I IFNs, TNF-alpha, and IFN-gamma, but show impaired phagocytic potential. LDGs induce significant endothelial cell cytotoxicity and synthesize sufficient levels of type I IFNs to disrupt the capacity of endothelial progenitor cells to differentiate into mature endothelial cells. LDG depletion restores the functional capacity of endothelial progenitor cells. We conclude that lupus LDGs are proinflammatory and display pathogenic features, including the capacity to synthesize type I IFNs. They may play an important dual role in premature cardiovascular disease development in systemic lupus erythematosus by simultaneously mediating enhanced vascular damage and inhibiting vascular repair.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Denny
authors.forename: Srilakshmi
authors.initials: S
authors.lastname: Yalavarthi
authors.forename: Wenpu
authors.initials: W
authors.lastname: Zhao
authors.forename: Seth G
authors.initials: SG
authors.lastname: Thacker
authors.forename: Marc
authors.initials: M
authors.lastname: Anderson
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Sandy
authors.forename: W Joseph
authors.initials: WJ
authors.lastname: McCune
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
mesh_terms: D000328:Adult; D002469:Cell Separation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007370:Interferon Type I / Q000096:biosynthesis* / Q000502:physiology; D016898:Interferon-alpha / Q000096:biosynthesis / Q000502:physiology; D007958:Leukocyte Count; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D023461:Myeloid Progenitor Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
chemical_list: D018836:Inflammation Mediators; D007370:Interferon Type I; D016898:Interferon-alpha