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Véronique Witko-Sarsat

Véronique Witko-Sarsat, PhD

Director of Research Inserm

Luc Mouthon, MD, PhD


Neutrophils and Vasculitis

Cochin Institute, Inserm U1016
Immunology-Hematology Department
Gustave Roussy Building (6th floor)
27 rue du Faubourg Saint Jacques
75014 Paris, France

tel: 33 1 40 51 66 56
fax: 33 1 40 51 65 35

Our team is focused on the mechanisms of inflammation in vascular diseases, and especially in autoimmune vasculitis. The pathogenesis of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides is poorly understood but it is consistent with a pivotal role for neutrophils since they are both effector cells responsible for endothelial damage and targets of autoimmunity. Our research is focused on the role of proteinase 3, the target autoantigen in Wegener’s granulomatosis. Pivotal  role of neutrophils in ANCA-associated vasculitis

Figure 1 (click to enlarge):
Pivotal role of neutrophils in ANCA-associated vasculitis (click to enlarge)

Proteinase 3 (PR3) is a membrane-associated protein and the neutrophil subset expressing membrane PR3 is increased in patients with vasculitis. We would like to understand : i) the structure/activity study to target specific domain of PR3 in order to modulate its function ; ii) the role of PR3 targets such as p21/waf1 that we have previously identified, in neutrophils ; iii) the role of membrane PR3 and its protein partners such as the phospholipidscramblase1 in the regulation of inflammation, apoptosis and macrophage phagocytosis.

In addition, because neutrophil apoptosis and their phagocytosis by macrophages constitute two pivotal steps in the inflammation resolution, we are studying key proteins involved in the regulation of the balance survival/apoptosis. Using a proteomic approach, we have identified novel cytosolic proteins playing a key role in neutrophil survival such as the actin-binding protein coronin-1A.

In the same line of research, we have discovered that neutrophils, despite their inability to proliferate, express high levels of PCNA exclusively in their cytosol where it is associated with procaspases to prevent their activation. Notably, cytosolic PCNA abundance decreased during apoptosis, increased during survival, thus controlling neutrophil fate. This novel survival pathway opens new research tracks and highlights a novel target to potentially modulate pathological inflammation. Considered  as a nuclear protein expressed in proliferating cells, PCNA can be detected  within the cytosol of neutrophils (here in red) where it controls their  survival. Nuclei are stained with Hoeschst.

Figure 2 (click to enlarge):
Considered as a nuclear protein expressed in proliferating cells, PCNA can be detected within the cytosol of neutrophils (here in red) where it controls their survival. Nuclei are stained with Hoeschst.

Recent publications

Witko-Sarsat, V., Pederzoli-Ribeil, M., Hirsh, E., Sozzani, S., Cassatella, M. Regulating neutrophil apoptosis: new players enter the game Trends Immunol 2011 in press.

Witko-Sarsat V, Mocek J, Bouayad D, Tamassia N, Ribeil JA, Candahl C, Davezac N, Reuter N, Mouthon L, Hermine O, Pederzoli-Ribeil M, Cassatella MA. Proliferating cell nuclear antigen acts as a cytoplasmic platform controlling human neutrophil survival. J Exp Med 2010 ; 207 : 2631-45.

Hajjar E, Broemstrup T, Kantari C, Witko-Sarsat V, Reuter N. Structures of human proteinase 3 and neutrophil elastase--so similar yet so different. FEBS J. 2010;277:2238-54.

Moriceau S, Lenoir G, Witko-Sarsat V. In cystic fibrosis homozygotes and heterozygotes, neutrophil apoptosis is delayed and modulated by diamide or roscovitine: evidence for an innate neutrophil disturbance J Innate Immunity. 2010; 260-6.

Witko-Sarsat V, Reuter N and Mouthon L. Interaction of proteinase 3 in the pathogenesis of Wegener’s granulomatosis. Curr Opin Rheumatol 2010, 22 : 1-7.

Moriceau S, Kantari C, Mocek J, Davezac N, Gabillet J, Guerrera IC, Brouillard F, Tondelier D, Sermet-Gaudelus I, Danel C, Lenoir G, Daniel S, Edelman A, Witko-Sarsat V. Coronin-1 is associated with neutrophil survival and is cleaved during apoptosis: Potential implication in neutrophils from cystic fibrosis patients. J Immunol. 2009;182:7254-7263.

Kantari C, Pederzoli-Ribeil M, Amir-Moazami O, Gausson-Dorey V, Moura IC, Lecomte MC, Benhamou M, Witko-Sarsat V. Proteinase 3, the Wegener autoantigen, is externalized during neutrophil apoptosis: evidence for a functional association with phospholipid scramblase 1, interference with macrophage phagocytosis. Blood. 2007;110:4086-95.

Dublet B, Ruello A, Pederzoli M, Hajjar E, Courbebaisse M, Canteloup S, Reuter N, Witko-Sarsat V. Cleavage of p21/WAF1/CIP1 by proteinase 3 modulates differentiation of a monocytic cell line. Molecular analysis of the cleavage site. J Biol Chem. 2005 280:30242-53.

Pederzoli M, Kantari C, Gausson V, Moriceau S, Witko-Sarsat V. Proteinase-3 induces procaspase-3 activation in the absence of apoptosis: potential role of this compartmentalized activation of membrane-associated procaspase-3 in neutrophils. J Immunol. 2005 174:6381-90.