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Kidney Int. 2019 Aug;96(2):397-408. doi: 10.1016/j.kint.2019.02.017. Epub 2019 Mar 4.

Proteomic analysis of neutrophils in ANCA-associated vasculitis reveals a dysregulation in proteinase 3-associated proteins such as annexin-A1 involved in apoptotic cell clearance.

Author information

1
INSERM U1016, Institut Cochin, Paris, France; CNRS-UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; University Hospital of Bern, Department of Rheumatology and Immunology, Switzerland.
2
INSERM U1016, Institut Cochin, Paris, France; CNRS-UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
3
Université Grenoble-Alpes, Centre Etude Atomique (CEA), CNRS, Institut Biologie Structurale (IBS), Grenoble, France.
4
Department of Biochemistry, Maastricht University, Cardiovascular Research Institute Maastricht, The Netherlands.
5
Department of Pneumology, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris (AP-HP), France.
6
Service de Médecine Interne et immunologie Clinique, CHU Dijon, France.
7
Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Nephrology, Hôpital Européen Georges Pompidou, AP-HP, France.
8
INSERM U1016, Institut Cochin, Paris, France; CNRS-UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Faculté de Médecine, pôle de Médecine Interne et centre de référence pour les vascularites nécrosantes et la sclérodermie systémique, AP-HP, France.
9
Faculté de Médecine, pôle de Médecine Interne et centre de référence pour les vascularites nécrosantes et la sclérodermie systémique, AP-HP, France.
10
The William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
11
INSERM U1016, Institut Cochin, Paris, France; CNRS-UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France. Electronic address: veronique.witko@inserm.fr.

Abstract

Granulomatosis with polyangiitis (GPA) is an autoimmune vasculitis associated with anti-neutrophil-cytoplasmic antibodies (ANCA) against proteinase 3 leading to kidney damage. Neutrophils from those patients have increased expression of membrane proteinase 3 during apoptosis. Here we examined whether neutrophils from patients with GPA have dysregulated protein expressions associated with apoptosis. A global proteomic analysis was performed comparing neutrophils from patients with GPA, with healthy individuals under basal conditions and during apoptosis. At disease onset, the cytosolic proteome of neutrophils of patients with GPA before treatment was significantly different from healthy controls, and this dysregulation was more pronounced following ex vivo apoptosis. Proteins involved in cell death/survival were altered in neutrophils of patients with GPA. Several proteins identified were PR3-binding partners involved in the clearance of apoptotic cells, namely calreticulin, annexin-A1 and phospholipid scramblase 1. These proteins form a platform at the membrane of apoptotic neutrophils in patients with GPA but not healthy individuals and this was associated with the clinical presentation of GPA. Thus, our study shows that neutrophils from patients with GPA have an intrinsic dysregulation in proteins involved in apoptotic cell clearance, which could contribute to the unabated inflammation and autoimmunity in GPA. Hence, harnessing these dysregulated pathways could lead to novel biomarkers and targeted therapeutic opportunities to treat kidney disease.

KEYWORDS:

annexin A; calreticulin; neutrophil; phospholipid scramblase 1; proteinase 3; vasculitis

PMID:
31142442
DOI:
10.1016/j.kint.2019.02.017
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