Neutrophil extracellular traps generation and degradation in patients with granulomatosis with polyangiitis and systemic lupus erythematosus

Pruchniak, Michał Przemysław; Ostafin, Magdalena; Wachowska, Malgorzata; Jakubaszek, Michał; Kwiatkowska, Brygida; Olesińska, Marzena; Życińska, Katarzyna; Demkow, Urszula

doi:10.1080/08916934.2019.1631812

Cited by 21 publications

(24 citation statements)

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“…Patients with GPA have been reported to generate NETs more efficiently than healthy individuals (22, 25). To examine whether differences in clinical patterning are correlated with the ability to release extracellular DNA, we tested the capacity of neutrophils to undergo NETosis in two patient cohorts: (1) patients with sGPA and (2) patients with H&N GPA.…”

Section: Resultsmentioning

confidence: 99%

“…NETs are actively released chromatin fibers containing DNA, histones, and neutrophil granule proteins, and are considered a critical component in the pathogenesis of ANCA-associated vasculitis (19, 20). Disordered regulation of NETosis, such as enhanced NET generation as well as reduced NET degradation, and the presentation of NET antigens by specific HLA haplotypes is postulated to play a role in the production of ANCAs (20–22). The interaction of the cell-surface semaphorin 4D, expressed on neutrophils, with plexin B2, expressed on vascular endothelial cells, inhibits NETs generation.…”

Section: Introductionmentioning

confidence: 99%

“…Also, NETs from ANCA-stimulated neutrophils have been reported to induce endothelial cell damage via alternative complement pathway activation with elevated C5a generation (24). Despite the increasing recognition of NETosis in the pathogenesis of ANCA-associated vasculitis, most of the studies are derived from MPO-ANCA associated vasculitis and only few studies of NETosis are available in patients with PR3-ANCA-related GPA (22, 25). Furthermore, although the DNA contained in NETs can activate innate immune cells such as monocytes and dendritic cells via Toll-like receptor (TLR) 9 (26), it remains unknown whether the pathogenic role of NETs in GPA is mechanistically linked to NET-dependent activation of inflammatory cells.…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil Extracellular Traps Induce Tissue-Invasive Monocytes in Granulomatosis With Polyangiitis

et al. 2019

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Objective: Granulomatosis with polyangiitis (GPA) is a multi-organ vasculitic syndrome typically associated with neutrophil extracellular trap (NET) formation and aggressive tissue inflammation. Manifestations in head and neck (H&N) GPA include septal perforations, saddle-nose deformities, bony erosions of the orbital and sinus walls, middle ear damage and epiglottitis, indicative of bone, cartilage, and connective tissue destruction. Whether H&N-centric lesions engage disease pathways distinctive from the ischemic tissue damage in the lungs, kidneys, skin, and peripheral nerves is unknown. We have compared inflammatory responses triggered by neutrophilic NETs in patients with H&N GPA and systemic GPA (sGPA).Methods: Neutrophils and monocytes were isolated from the peripheral blood of patients with H&N GPA, sGPA, and age/gender matched healthy individuals. Neutrophil NETosis was induced. NETs were isolated and cocultured with monocytes. Gene induction was quantified by RT-PCR, protein upregulation by flow cytometry. Tissue invasiveness of monocytes was measured in a 3D collagen matrix system. Expression of MMP-9 in tissue-residing macrophages was assessed by immunohistochemistry in tissue biopsies.Results: Neutrophils from H&N GPA patients showed more intense NETosis with higher frequencies of netting neutrophils (P < 0.001) and release of higher amounts of NETs (P < 0.001). Isolated NETs from H&N GPA functioned as an inducer of danger-associated molecular patterns in monocytes; specifically, alarmin S100A9. NET-induced upregulation of monocyte S100A9 required recognition of DNA. S100A9 release resulted in the induction of metalloproteinases, including MMP-9, and enabled monocytes to invade into extracellular matrix. Anti-MMP-9 treatment attenuated the tissue invasiveness of monocytes primed with NETs from H&N GPA patients. MMP-9-producing macrophages dominated the tissue infiltrates in naso-sinal biopsies from H&N GPA patients.Conclusion: Distinct disease patterns in GPA are associated with differences in NET formation and NET content. H&N GPA patients with midline cartilaginous and bony lesions are highly efficient in generating NETs. H&N GPA neutrophils trigger the induction of the alarmin S100A9, followed by production of MMP-9, endowing monocytes with tissue-invasive capabilities.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neutrophil Extracellular Traps Induce Tissue-Invasive Monocytes in Granulomatosis With Polyangiitis

et al. 2019

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“…This release explains the increased levels of cfDNA found in plasma from patients with SLE. Moreover, most of the patients with SLE have a reduced ability to degrade NETs [ 42 ], and the prolonged presence of NETs in plasma could promote a rupture of immune tolerance as well as increase tissue damage [ 45 ]. These events lead to the formation of an amplification loop, in which NET components induce autoantibodies, leading to the formation of more immune complexes which, in turn, perpetuate NET formation.…”

Section: Discussionmentioning

confidence: 99%

Insights into the Procoagulant Profile of Patients with Systemic Lupus Erythematosus without Antiphospholipid Antibodies

Manzano

Bello

Sanz

et al. 2020

JCM

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We aimed to identify the key players in the prothrombotic profile of patients with systemic lupus erythematosus (SLE) not mediated by antiphospholipid antibodies, as well as the potential utility of global coagulation tests to characterize hemostasis in these patients. Patients with SLE without antiphospholipid antibodies and without signs of thrombosis were included. The kinetics of clot formation were determined by ROTEM®. Platelet activation markers were determined by flow cytometry. Thrombin generation associated with Neutrophil Extracellular Traps (NETs) and microparticles (MPs) was measured by calibrated automated thrombogram (CAT). The plasma levels of PAI-1 were also determined. ROTEM® showed a procoagulant profile in SLE patients. SLE patients had activated platelets and more leukocyte/platelet aggregates at basal conditions. The plasma PAI-1 and platelet aggregates correlated with several ROTEM® parameters. The thrombin generation associated withthe tissue factor (TF) content of MPs and with NETs was increased. Our results suggest the utility of global tests for studying hemostasis in SLE patients because they detect their procoagulant profile, despite having had neither antiphospholipid antibodies nor any previous thrombotic event. A global appraisal of hemostasis should, if possible, be incorporated into clinical practice to detect the risk of a thrombotic event in patients with SLE and to consequently act to prevent its occurrence.

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“…Some patients with active lupus or lupus nephritis have a deficiency in DNase 1 activity and/or anti-NET antibodies that inhibit DNase effect (23, 59, 60), leading to abnormal NET accumulation. This prolonged presence of NETs could favor rupture of tolerance as well as increase tissue damage (61). Another interesting element is that the composition of NETs from SLE patients is different from that of healthy controls.…”

Section: Immune Complex-induced Nets Can Trigger and Perpetuate Variomentioning

confidence: 99%

Neutrophil Extracellular Traps in Autoimmunity and Allergy: Immune Complexes at Work

et al. 2019

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Neutrophil extracellular traps (NETs) have been initially described as main actors in host defense owing to their ability to immobilize and sometimes kill microorganisms. Subsequent studies have demonstrated their implication in the pathophysiology of various diseases, due to the toxic effects of their main components on surrounding tissues. Several distinct NETosis pathways have been described in response to various triggers. Among these triggers, IgG immune complexes (IC) play an important role since they induce robust NET release upon binding to activating FcγRs on neutrophils. Few in vitro studies have documented the mechanisms of IC-induced NET release and evidence about the partners involved is controversial. In vivo, animal models and clinical studies have strongly suggested the importance of IgG IC-induced NET release for autoimmunity and anaphylaxis. In this review, we will focus on two autoimmune diseases in which NETs are undoubtedly major players, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). We will also discuss anaphylaxis as another example of disease recently associated with IC-induced NET release. Understanding the role of IC-induced NETs in these settings will pave the way for new diagnostic tools and therapeutic strategies.

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Neutrophil extracellular traps generation and degradation in patients with granulomatosis with polyangiitis and systemic lupus erythematosus

Cited by 21 publications

References 70 publications

Neutrophil Extracellular Traps Induce Tissue-Invasive Monocytes in Granulomatosis With Polyangiitis

Neutrophil Extracellular Traps Induce Tissue-Invasive Monocytes in Granulomatosis With Polyangiitis

Insights into the Procoagulant Profile of Patients with Systemic Lupus Erythematosus without Antiphospholipid Antibodies

Neutrophil Extracellular Traps in Autoimmunity and Allergy: Immune Complexes at Work

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