TY - JOUR
T1 - 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
AU - Everts-Graber, Judith
AU - Martin, Katherine R.
AU - Thieblemont, Nathalie
AU - Mocek, Julie
AU - Roccabianca, Arnaud
AU - Chafey, Philippe
AU - Le Gall, Morgane
AU - Tacnet-Delorme, Pascale
AU - Reutelingsperger, Chris P.
AU - Naccache, Jean-Marc
AU - Bonnotte, Bernard
AU - Karras, Alexandre
AU - Puechal, Xavier
AU - Guillevin, Loic
AU - Terrier, Benjamin
AU - Frachet, Philippe
AU - Perretti, Mauro
AU - Mouthon, Luc
AU - Witko-Sarsat, Veronique
N1 - Funding Information:
This work was supported by a research grant from the French Ministry of Health (PHRC National 2010-AOM10055) and sponsored by the Assistance Publique-Hopitaux de Paris; Investissements d’Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Labex INFLAMEX, DHU-AUTHORS, the Chancellerie des Universités de Paris (Legs Poix VWS), and the Arthritis Foundation. KRM was supported by funding from the Labex Inflamex and from NHMRC (Early Career Research Fellowship GNT1092602); JEG was supported by a grant of the Swiss Society of Rheumatology; The platforms of the Grenoble Instruct- ERIC center: ISBG; UMS 3518 CNRS-CEA-UJF-EMBL (PF) with support from FRISBI: ANR-10-INSB-05-02 (PF) and GRAL: ANR-10-LABX-49-01 (PF) within the Grenoble Partnership for Structural Biology (PSB).
Funding Information:
This work was supported by a research grant from the French Ministry of Health (PHRC National 2010-AOM10055) and sponsored by the Assistance Publique-Hopitaux de Paris; Investissements d'Avenir programme ANR-11-IDEX-0005-02, Sorbonne Paris Cite, Labex INFLAMEX, DHU-AUTHORS, the Chancellerie des Universités de Paris (Legs Poix VWS), and the Arthritis Foundation. KRM was supported by funding from the Labex Inflamex and from NHMRC (Early Career Research Fellowship GNT1092602); JEG was supported by a grant of the Swiss Society of Rheumatology; The platforms of the Grenoble Instruct- ERIC center: ISBG; UMS 3518 CNRS-CEA-UJF-EMBL (PF) with support from FRISBI: ANR-10-INSB-05-02 (PF) and GRAL: ANR-10-LABX-49-01 (PF) within the Grenoble Partnership for Structural Biology (PSB). We thank the clinicians for patient recruitment: Amélie Servettaz, Isabelle Marie, Mohamed Hamidou, Antoine Neel, Gilles Hayem, Thomas Hanslik, Philippe Rémy, Jonathan London, Pascal Cohen, Jacques Cadranel, and Maxime Samson; Séverine Aït-el-Ghaz-Poignant, Hicham Kardaoui (URC); The 3P5-proteomic and CyBio facilities (Cochin Institute); EFS (Saint-Antoine Hospital, Paris).
Publisher Copyright:
© 2019 International Society of Nephrology
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
KW - annexin A
KW - calreticulin
KW - neutrophil
KW - phospholipid scramblase 1
KW - proteinase 3
KW - vasculitis
KW - MEMBRANE PROTEINASE-3
KW - AUTOANTIGEN GENES
KW - EXPRESSION
KW - GRANULOMATOSIS
KW - CALPROTECTIN
KW - PHAGOCYTOSIS
KW - POLYANGIITIS
KW - RELAPSE
KW - LIGAND
U2 - 10.1016/j.kint.2019.02.017
DO - 10.1016/j.kint.2019.02.017
M3 - Article
C2 - 31142442
SN - 0085-2538
VL - 96
SP - 397
EP - 408
JO - Kidney International
JF - Kidney International
IS - 2
ER -