期刊
JOURNAL OF IMMUNOLOGY
卷 187, 期 1, 页码 538-552出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1100450
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资金
- National Institutes of Health [HL088419]
- Arthritis Foundation
- University of Michigan
- Anthony Gramer Fund in Inflammation Research
- Babcock Research Endowment
- Training Grant in Cell and Molecular Dermatology [5T32AR007197]
- National Institutes of Health through the University of Michigan's Cancer Center [P30 CA46592]
- Rheumatic Disease Core Center [P30 AR48310]
- Applied Systems Biology Core in the O'Brien Renal Center [P30 DK081943]
An abnormal neutrophil subset has been identified in the PBMC fractions from lupus patients. We have proposed that these low-density granulocytes (LDGs) play an important role in lupus pathogenesis by damaging endothelial cells and synthesizing increased levels of proinflammatory cytokines and type I IFNs. To directly establish LDGs as a distinct neutrophil subset, their gene array profiles were compared with those of autologous normal-density neutrophils and control neutrophils. LDGs significantly overexpress mRNA of various immunostimulatory bactericidal proteins and alarmins, relative to lupus and control neutrophils. In contrast, gene profiles of lupus normal-density neutrophils do not differ from those of controls. LDGs have heightened capacity to synthesize neutrophils extracellular traps (NETs), which display increased externalization of bactericidal, immunostimulatory proteins, and autoantigens, including LL-37, IL-17, and dsDNA. Through NETosis, LDGs have increased capacity to kill endothelial cells and to stimulate IFN-alpha synthesis by plasmacytoid dendritic cells. Affected skin and kidneys from lupus patients are infiltrated by netting neutrophils, which expose LL-37 and dsDNA. Tissue NETosis is associated with increased anti-dsDNA in sera. These results expand the potential pathogenic roles of aberrant lupus neutrophils and suggest that dysregulation of NET formation and its subsequent responses may play a prominent deleterious role. The Journal of Immunology, 2011, 187: 538-552.
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