Team :Neutrophils and Vasculitis
Team leader : Véronique WITKO-SARSAT
Co-Director : Luc Mouthon
Our team is focused on the mechanisms of inflammation and tissue remodeling in vascular diseases, and especially in autoimmune vasculitis. Our research projects are focused on basic molecular and cellular aspects as well as on clinical implications.
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.
Neutrophils are key players in innate immunity, having both an essential microbicidal function and a pro-inflammatory potential. Therefore, neutrophil apoptosis and their phagocytosis by macrophages constitute two pivotal steps in the inflammation resolution, and are the focus of the Research project 1 in Véronique Witko-Sarsat’s group. 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. Indeed, coronin-1A acting as a new « anti-apoptotic » proteins, can greatly promote neutrophil survival and favor neutrophil persistence at the inflammation sites.
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.
Systemic vasculitides include a heterogeneous group of systemic diseases characterized by vascular necrosis and perivascular inflammation in small vessels. Notably, the clinical presentation of these diseases is different and varies according to the localization and the vessel size involved. ANCA-associated vasculitides involve small vessels and comprise microscopic polyangiitis (MPA), Churg-Strauss syndrome and Wegener’s granulomatosis. In both microscopic polyangiitis and Churg-Strauss syndrome, myeloperoxidase is the main target antigen, whereas Wegener’s granulomatosis is strongly associated with ANCA directed against proteinase 3 (PR3).
Notably, neutrophils from patients with Wegener’s granulomatosis have disturbed functions, an aberrant gene expression profile and strongly expressed membrane-associated proteinase 3. In Wegener’s granulomatosis, neutrophils strongly express membrane-associated proteinase 3, which constitutes a pro-inflammatory factor. Although proteinase 3 appears to play an instrumental role in Wegener’s granulomatosis pathophysiology, its functions in neutrophils are not well understood. Our team has shown that membrane PR3 expression occurred during apoptosis and that it inhibited the phagocytois of apoptotic neutrophils by macrophages, thus potentiating inflammation and potentially autoimmunity. The molecular, structural and functional study of neutrophil proteinase 3 and its clinical implications constitute the Research project 2.
In autoimmune vasculitis, immune perturbations extend to other target cells such as endothelial cells with potential deleterious effects. Notably, endothelial cells show an activated phenotype and are the target of autoimmunity. The group of Luc Mouthon is focused on the cellular and immunological aspects of vasculitis pathophysiology and the identification of the proteins that are targets of anti-endothelial and anti-vascular smooth muscle cells autoantibodies. The potential pathogenic role of these autoantibodies are studied in other vascular diseases such as Horton disease, arterial pulmonary hypertension ans systemic sclerosis and constitutes the Research project 3.
The team takes the opportunity of the very specific recruitment of patients with systemic vasculitis of the “National reference center for systemic vasculitidis and systemic sclerosis” at Cochin Hospital. In addition the strong clinical interface with the Department of Internal Medicine directed by Pr Loïc
Guillevin at the Cochin Hospital as well the interaction with other clinical Departments is a positive point to carry out our multidisciplinary project involving both basic and translational research.