Cleaved N-terminal histone tails distinguish between NADPH oxidase (NOX)-dependent and NOX-independent pathways of neutrophil extracellular trap formation

Pieterse, Elmar; Rother, Nils; Yanginlar, Cansu; Gerretsen, Jelle; Boeltz, Sebastian; Muñoz, Luis; Herrmann, Martin; Pickkers, Peter; Hilbrands, Luuk B.; Vlag, Johan van der

doi:10.1136/annrheumdis-2018-213223

Cited by 76 publications

(89 citation statements)

References 51 publications

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“…The characteristics of these “pure” RNP ICx, which are distinct from the heterogenous autoantibodies and ICx derived from SLE patient serum investigated in the present study, likely explain the discrepancy with regard to whether or not NADPH oxidase is involved. Indeed, our finding of NADPH oxidase–independent formation of NETs in SLE was recently confirmed by others in studies that utilized a novel method for discriminating between NADPH oxidase–dependent and –independent NET formation .…”

Section: Discussionsupporting

confidence: 81%

“…In contrast, non‐lytic NET formation is typically induced within minutes, and can be triggered by lipopolysaccharide (LPS) , specific bacterial products , Toll‐like receptor 4 (TLR‐4)–activated platelets , or complement proteins together with TLR‐2 ligands and SLE‐specific ICx. Non‐lytic NET formation can be independent of NADPH oxidase , but some studies have shown that NADPH oxidase can be involved . Importantly, the plasma membrane is not disrupted and NETs are released via vesicular transport while remaining viable, and typically contain oxidized mtDNA .…”

Section: Discussionmentioning

confidence: 99%

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Intrinsically Distinct Role of Neutrophil Extracellular Trap Formation in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Compared to Systemic Lupus Erythematosus

Dam

Kraaij

Kamerling

et al. 2019

Arthritis & Rheumatology

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Objective. Different studies have demonstrated that neutrophil extracellular traps (NETs) may be involved in the pathophysiology of both antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). AAV and SLE are clinically and pathologically divergent autoimmune diseases with different autoantibodies. However, the respective autoantigens recognized in AAV and SLE have been shown to be an intricate part of NETs. This study aimed to examine whether the mechanisms of NET formation and the composition of NETs are distinct between AAV and SLE.Methods. To investigate this hypothesis, healthy neutrophils were stimulated with serum from patients with AAV (n = 80) and patients with SLE (n = 59), and the mechanisms of NET formation and NET composition were compared.Results. Both patients with AAV and patients with SLE had excessive NET formation, which correlated with the extent of disease activity (in AAV r = 0.5, P < 0.0001; in SLE r = 0.35, P < 0.01). Lytic NET formation over several hours was observed in patients with AAV, as compared to rapid (within minutes), non-lytic NET formation coinciding with clustering of neutrophils in patients with SLE. AAV-induced NET formation was triggered independent of IgG ANCAs, whereas SLE immune complexes (ICx) induced NET formation through Fcγ receptor signaling. AAV-induced NET formation was dependent on reactive oxygen species and peptidyl arginine deaminases, and AAV-induced NETs were enriched for citrullinated histones (mean ± SEM 23 ± 2%). In contrast, SLE-induced NETs had immunogenic properties, including binding with high mobility group box chromosomal protein 1 (mean ± SEM 30 ± 3%) and enrichment for oxidized mitochondrial DNA, and were involved in ICx formation.Conclusion. The morphologic features, kinetics, induction pathways, and composition of excessive NET formation are all intrinsically distinct in AAV compared to SLE. Recognizing the diversity of NET formation between AAV and SLE provides a better understanding of the pathophysiologic role of NETs in these different autoimmune diseases.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Intrinsically Distinct Role of Neutrophil Extracellular Trap Formation in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Compared to Systemic Lupus Erythematosus

Dam

Kraaij

Kamerling

et al. 2019

Arthritis & Rheumatology

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“…Experimental models of SLE, although with several limitations, tend to exclude a pathogenic role for NETosis in SLE 42,43 , apparently in accordance with the finding that NETosis-defective individuals (with impaired NADPH activity) are more prone to lupus-like disease than HD [39][40][41][42][43] . On the other hand, NET-like structures form in both a NADPH-dependent, or independent manner, and NET-like cell death due to autoantibodies does not seem to rely on NADPH activity 40,[44][45][46][47] . In our experiments, we observe that patient-derived anti-LL37 antibodies generated in vitro stimulate neutrophil extrusion of DNA filaments decorated by LL37.…”

Section: Discussionmentioning

confidence: 99%

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Lande

Palazzo

Gestermann

et al. 2020

Sci Rep

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LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(T fH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications. Systemic Lupus Erythematosus (SLE) is an autoimmune disease with a prevalence of about 20-50 cases per 100,000 in Northern Europe and USA 1 , characterized by immune-complex formation and deposition, which result in inflammation and tissue damage. In SLE, altered clearance of dying cells determines persistent exposure of autoantigens and activation of antigen-presenting cells (APCs), mainly via Toll-like receptors (TLR), thus favoring adaptive immune response licensing 1-3. SLE autoantibodies are preferentially directed against

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“…Neutrophil extracellular traps (NETs), an antimicrobial form of neutrophil death, were the first mechanism proposed to be associated with the production of citrullinated autoantigens in RA . This form of cell death is present in the RA joint, in vitro evidence suggests that neutrophils from patients with RA have increased susceptibility to form NETs, and in vivo evidence suggests that the formation of NETs is increased in RA . An association between NETs and citrullination was initially proposed by the finding that PAD4‐mediated citrullination of histones was necessary for NET formation in mice .…”

Section: Discovering the Origin Of The Intracellular Citrullinome In Ramentioning

confidence: 99%

“…76 This form of cell death is present in the RA joint, 76 in vitro evidence suggests that neutrophils from patients with RA have increased susceptibility to form NETs, 76 and in vivo evidence suggests that the formation of NETs is increased in RA. 80 An association between NETs and citrullination was initially proposed by the finding that PAD4-mediated citrullination of histones was necessary for NET formation in mice. 81 Later, this finding was erroneously taken as direct evidence that citrullination, particularly of histones, is a hallmark and exclusive marker of NETs.…”

Section: Neutrophil Extracellular Traps As Source Of the Ra Citrullmentioning

confidence: 99%

Insights into the study and origin of the citrullinome in rheumatoid arthritis

Fert-Bober

Darrah

Andrade

2019

Immunological Reviews

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The presence of autoantibodies and autoreactive T cells to citrullinated proteins and citrullinating enzymes in patients with rheumatoid arthritis (RA), together with the accumulation of citrullinated proteins in rheumatoid joints, provides substantial evidence that dysregulated citrullination is a hallmark feature of RA. However, understanding mechanisms that dysregulate citrullination in RA has important challenges. Citrullination is a normal process in immune and non‐immune cells, which is likely activated by different conditions (eg, inflammation) with no pathogenic consequences. In a complex inflammatory environment such as the RA joint, unique strategies are therefore required to dissect specific mechanisms involved in the abnormal production of citrullinated proteins. Here, we will review current models of citrullination in RA and discuss critical components that, in our view, are relevant to understanding the accumulation of citrullinated proteins in the RA joint, collectively referred to as the RA citrullinome. In particular, we will focus on potential caveats in the study of citrullination in RA and will highlight methods to precisely detect citrullinated proteins in complex biological samples, which is a confirmatory approach to mechanistically link the RA citrullinome with unique pathogenic pathways in RA.

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Cleaved N-terminal histone tails distinguish between NADPH oxidase (NOX)-dependent and NOX-independent pathways of neutrophil extracellular trap formation

Abstract: These results indicate heterogeneity in NET-forming pathways and highlight the need for disease-specific strategies to prevent NET-mediated pathology.

Cited by 76 publications

References 51 publications

Intrinsically Distinct Role of Neutrophil Extracellular Trap Formation in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Compared to Systemic Lupus Erythematosus

Intrinsically Distinct Role of Neutrophil Extracellular Trap Formation in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis Compared to Systemic Lupus Erythematosus

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus

Insights into the study and origin of the citrullinome in rheumatoid arthritis

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