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Abstract Number: 2789

Neutrophil Extracellular Traps Induce Tissue-Invasive Macrophages in Granulomatosis with Polyangiitis Dominated by Ear, Nose and Throat Manifestations

Mitsuhiro Akiyama1, Nour Ibrahim 2, Markus Zeisbrich 1, Peter Hwang 1, Jorg Goronzy 1 and Cornelia Weyand 1, 1Stanford University, Stanford, CA, 2Stanford University, Stanford University

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: monocytes and ANCA, NETosis, Neutrophil Extracellular Traps, Wegener's granulomatosis

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Session Information

Date: Tuesday, November 12, 2019

Session Title: 5T096: Vasculitis – ANCA-Associated II (2786–2791)

Session Type: ACR Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis characterized by acute and chronic tissue destruction in the nose, sinuses, lungs and kidneys. In a subset of patients, tissue inflammation predominantly occurs in the ear, nose, throat and eye (ENT-dominated) manifesting with tissue-invasive and space-consuming lesions, such as saddlenose, septal perforation, orbital and ear bony wall destruction, and epiglottitis. ENT-dominated GPA is often chronic-relapsing and associated with autoantibodies against PR-3. A critical element in the pathogenesis of GPA is the production of neutrophil extracellar traps (NETs) from dying neutrophils. Whether NET-related pathology is different in distinct subsets of GPA patients is unknown. We have compared NET-induced inflammatory responses in patients with systemic GPA versus ENT-dominated GPA.

Methods: Patients with renal versus ENT-dominated GPA (rGPA; ENT-GPA) were recruited from a database that prospectively follows vasculitis patients. Patients with disease duration of >5 years and matched for immunosuppressive therapy were enrolled. Neutrophils and monocytes from rGPA, ENT-GPA and age-gender matched healthy donors were isolated from peripheral blood. NETosis was induced in isolated neutrophils and quantified with SYTOX green (ThermoFisher) and analyzed by flow cytometry. Isolated NETS were cocultured with monocyte-derived macrophages and the induction of pro-inflammatory mediators was examined by RT-PCR and flow cytometry. Tissue invasiveness of monocytes/macrophages was measured in a 3D matrix system.

Results: Neutrophils from patients with ENT-GPA had more intense NETosis with higher frequencies of netting neutrophils (P < 0.01) and more NETs released (P < 0.01). Purified NETs functioned as potent activators of monocytes and macrophages and induced a pro-inflammatory phenotype. Netting neutrophils from ENT-GPA were more efficient in upregulating pro-inflammatory cytokines in monocytes/macrophages (P < 0.01) when compared to neutrophils isolated from rGPA or age-matched controls. Measurements of matrix-invasive capacity of monocytes and macrophages exposed to control and patient-derived NETs revealed that ENT-GPA-derived NETs were able to induce monocytes and macrophages that were highly efficient in tissue invasion.

Conclusion: Neutrophils from patients with specified GPA disease patterns differ in NET formation. Highly efficient NETosis is associated with predominance of ENT manifestations. NETs are recognized by monocytes and macrophages and act as pro-inflammatory triggers. NETs derived from ENT-GPA patients are strong inducers of a tissue-destructive and invasive phenotype, reminiscent of the clinical manifestations in ENT-dominated GPA.


Disclosure: M. Akiyama, None; N. Ibrahim, None; M. Zeisbrich, None; P. Hwang, None; J. Goronzy, None; C. Weyand, Kiniska Pharmaceuticals, 2.

To cite this abstract in AMA style:

Akiyama M, Ibrahim N, Zeisbrich M, Hwang P, Goronzy J, Weyand C. Neutrophil Extracellular Traps Induce Tissue-Invasive Macrophages in Granulomatosis with Polyangiitis Dominated by Ear, Nose and Throat Manifestations [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/neutrophil-extracellular-traps-induce-tissue-invasive-macrophages-in-granulomatosis-with-polyangiitis-dominated-by-ear-nose-and-throat-manifestations/. Accessed April 17, 2021.
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