Netting neutrophils induce endothelial damage, infiltrate tissues and expose immunostimulatory molecules in systemic lupus erythematosus

By Eneida C. Villanueva, S. Yalavarthi, C. Berthier, J. Hodgin, R. Khandpur, A. M. Lin, Cory J. Rubin, Wenpu Zhao, Stephen H. Olsen, M. Klinker and 7 more. Journal of Immunology, 2011

1,203 citations recorded by the source corpus.

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-α 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.

Subfields: Immunology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/2dfcfacde16cadff90701cfef0cc8195a0946bcf

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In Immunology

1. P. Kubes
2. C. Rosales
3. C. Jenne
4. B. McDonald
5. B. Yipp
6. M. Radic
7. M. Kaplan

In Pulmonary and Respiratory Medicine

1. P. Kubes

Citations in the corpus

• Personalized Immunomonitoring Uncovers Molecular Networks That Stratify Lupus Patients (2016, neutral): “In lupus, these cells are primed by IFN and release both pro-inflammatory mediators and interferogenic DNA when exposed to SLE ICs (Garcia-Romo et al., 2011; Hakkim et al., 2010; Villanueva et al., 2011).”
• Neutrophil extracellular traps (NETs): Double-edged swords of innate immunity (2012, background): “Furthermore, netting neutrophils may play important roles in the promotion of atherosclerosis, thrombosis, and other vascular complications (21, 65).”
• Nr4a1-Dependent Ly6Clow Monocytes Monitor Endothelial Cells and Orchestrate Their Disposal (2013, neutral): “Neutrophils damage endothelial cells when activated (Villanueva et al., 2011; Westlin and Gimbrone, 1993).”
• Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. (2012, background): “Numerous reports have demonstrated roles for NETs in tissue damage and disease pathology in a number of infectious, inflammatory, and autoimmune diseases (Clark et al., 2007; Fuchs et al., 2010; Kessenbrock et al., 2009; Villanueva et al., 2011).”
• A Myeloperoxidase-Containing Complex Regulates Neutrophil Elastase Release and Actin Dynamics during NETosis (2014, neutral): “…of NET degradation is linked to several diseases, including cystic fibrosis, preeclampsia, autoimmunity, and vascular diseases (Garcia-Romo et al., 2011; Hakkim et al., 2010; Kessen-brock et al., 2009; Khandpur et al., 2013; Lande et al., 2011; Papayannopoulos et al., 2011; Villanueva et al., 2011).”
• Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones (2012, background): “as preeclampsia, small-vessel vasculitis and systemic lupus erythematosus [26,28,29,31,60,61].”
• Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation (2015, neutral): “To better understand the mechanism of these molecules, we solved crystal structures of human PAD4 C645A complexed with either GSK199 at 3.3 Å or the closely related inhibitor GSK147 ( 5 ) at 3.1 Å (Supplementary Table 3).”
• NETosis: how vital is it? (2013, background): “Further investigation has revealed that subsets of neutrophils, expanded in lupus patients, are prone to NETosis, potentially due to overexpression of the NET-dependent proteins MPO and elastase.(124) NET components subsequently damage the vasculature, activate plasmacytoid dendritic cells via TLR9 ”
• NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis (2013, methodology): “Scien NETs by proteomic analyses by us and other groups (25), whereas it is readily identified in these structures by other techniques (14).”
• Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury (2015, background): “Several chronic inflammatory disease conditions are characterized by a sustained influx of neutrophils, such as CF, chronic obstructive pulmonary disease, rheumatoid arthritis, nephritis, SLE, and cardiovascular diseases.”
• Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? (2018, background): “Hence, neutrophils from diabetic patients (Wong et al., 2015) and from systemic lupus erythematosus (SLE) patients (Garcia-Romo et al., 2011; Villanueva et al., 2011) have been shown to be more prone to NET formation.”