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    Team: Neutrophils and Vasculitis

    Team leader

    researcher-portrait_veronique-witko-sarsat

    The research project of the team explores the biology of neutrophil which is a key cell in inflammation and in the defense against bacteria. However, if activated neutrophils are not properly eliminated, they can damage the host tissues.

    Our team studies neutrophils in autoimmune vasculitis because they play a pivotal role in the immune dysregulation and in the destruction of small vessels.

    The new mechanisms in the control of neutrophil activation that we uncover could be relevant in other diseases in which neutrophils are involved like in arthritis, pulmonary inflammation, septic shock and cancer.

     

     

    Autoimmune vasculitides associated with anti-neutrophil cytoplasmic antibody (called ANCA) are examples of systemic inflammation in which the persistence of activated neutrophils at the site of inflammation hinders the resolution of inflammation leading to small vessel necrosis.

    The team examines the biology of neutrophils to understand their effector mechanisms (particularly the oxidants and the proteinases) associated with the signalling pathways regulating different types of death (Léa Remy-Tourneur’s project) (Research project 1). Our work is also focused on the structural and functional study of proteinase 3, the target antigen of ANCA in a particular type of vasculitis named granulomatosis with polyangiitis (GPA) (formerly known as Wegener disease) (Research project 2). The proteinase 3 expressed at the surface of apoptotic neutrophils is considered as a « danger signal » by macrophages thereby stimulating innate immunity (Nathalie Thieblemont’s projet). We also propose to decipher the interactions between neutrophils and other immune cells, for instance B cells and innate lymphocytes (ILC2) (Benjamin Terrier’s project) (Research project 3). Interactions between immune and vascular cells (endothelial cells, smooth muscle vascular cells) are involved in the inflammation and the vascular remodeling are also studied (Luc Mouthon’s project) (Research project 4).

    The team benefits from 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 at the Cochin Hospital as well the interactions with other clinical Departments, particularly with the Pneumology Department (CLIC : for our investigations of neutrophils in cystic fibrosis patients, are positive points to carry out our multidisciplinary project involving both basic and translational research.

     

    Network

    The team is part of the Excellence Network Labex Inflamex since 2011

    The team is part of the Groupe Français Etude des Vascularites (GFEV)

    Scientific societies :

    Véronique Witko-Sarsat : Member of the Conseil d’Administration of the  Société Française d’Immunologie (2015-2018) ; GREMI (Groupe Recherche sur les Médiateurs de l’inflammation) : Vice-president;  Committee; Councillor at the Society for Leukocyte Biology (2015-2020). Young researchers from the Institut Cochin awarded by the Society for Leukocyte Biology.

    Luc Mouthon: President of the Groupe francophone de recherche sur la sclérodermie (GFRS); Directeur du Centre de Référence Maladies Auto-immunes et Maladies Systémiques Rares,s, Hôpital Cochin

     

    Meetings and international visibility

    The 6th Institut Cochin Symposium : « From cell death to autoimmunity » December 15th 2015,  Amphithéâtre Luton, Cochin Hospital

    The Phagocyte Worshop at the 50th Annual Scientific Meeting of the European Society for Clinical Investigation Paris, France 27 – 29 May 2016 on the campus of the Cochin Hospital.

    The 18th International Vasculitis & ANCA Workshop 2017, Tokyo, Japon (member of the scientific committee)

    Véronique Witko-Sarsat is a speaker at the 52th annual meeting of the Society for Leukocyte Biology "Tissue specific immunity: translating our discoveries" (Boston, 2019, November 15-18). Meet the speakers here.

    Editorial activities

    Véronique Witko-Sarsat is member of the Editorial board of  Journal of Innate Immunity 

    Recents Editorials

    Inflammasome activation: Neutrophils go their own way.
    Tourneur L, Witko-Sarsat V. J Leukoc Biol. 2019 Mar;105(3):433-436

    From Starfish Oocytes to Inflammation: The Unforeseeable Destiny of Roscovitine in Cystic Fibrosis. J Innate Immun. 2016;8(4):327-9.

    Autophagy and innate immunity. J Innate Immun. 2013;5(5):425-6.

     

    Main publications

    The team has recenty published:
    • Ohayon D, De Chiara A, Dang PM, Thieblemont N, Chatfield S, Marzaioli V, Burgener SS, Mocek J, Candalh C, Pintard C, Tacnet-Delorme P, Renault G, Lagoutte I, Favier M, Walker F, Hurtado-Nedelec M, Desplancq D, Weiss E, Benarafa C, Housset D, Marie JC, Frachet P, El-Benna J, Witko-Sarsat V. Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils. J Exp Med. 2019 Sep 6. pii: jem.20180371.
    • Everts-Graber J, Martin KR, Thieblemont N, Mocek J, Roccabianca A, Chafey P, Le Gall M, Tacnet-Delorme P, Reutelingsperger CP, Naccache JM, Bonnotte B, Karras A, Puéchal X, Guillevin L, Terrier B, Frachet P, Perretti M, Mouthon L, Witko-Sarsat V. 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. Kidney Int. 2019; 96:397-408.
    • Mouasni S, Gonzalez V, Schmitt A, Bennana E, Guillonneau F, Mistou S, Avouac J, Ea HK, Devauchelle V, Gottenberg JE, Chiocchia G, Tourneur L. The classical NLRP3 inflammasome controls FADD unconventional secretion through microvesicle shedding. Cell Death Dis. 2019; 10:190.
    • Hadjadj J, Canaud G, Mirault T, Samson M, Bruneval P, Régent A, Goulvestre C, Witko-Sarsat V, Costedoat-Chalumeau N, Guillevin L, Mouthon L, Terrier B; French Vasculitis Study Group. mTOR pathway is activated in endothelial cells from patients with Takayasu arteritis and is modulated by serum immunoglobulin G. Rheumatology. 2018;57:1011-1020.
    • Martin KR, Pederzoli-Ribeil M, Pacreau E, Burgener SS, Dahdah A, Candalh C, Lauret E, Foretz M, Mouthon L, Lucas B, Thieblemont N, Benarafa C, Launay P, Witko-Sarsat V.  Transgenic mice expressing human proteinase 3 exhibit sustained neutrophil-associated peritonitis.  Immunol. 2017; 199:3914-3924.
    • Ohayon D, De Chiara A, Chapuis N, Candalh C, Mocek J, Ribeil JA, Haddaoui L, Ifrah N, Hermine O, Bouillaud F, Frachet P, Bouscary D and Witko-Sarsat V. Active nuclear export of PCNA is a key mechanism to connect glycolysis and cell survival in acute myeloid leukemia. Sci Rep. 2016; 6:35561. doi: 10.1038/srep35561.
    • Millet A, Martin KR, Bonnefoy F, Saas P, Mocek J, Alkan M, Terrier B, Kerstein A, Tamassia N, Satyanarayanan SK, Ariel A, Ribeil JA, Guillevin L, Cassatella MA, Mueller A, Thieblemont N, Lamprecht P, Mouthon L, Perruche S, Witko-Sarsat V. Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis. J Clin Invest. 2015; 125:4107-21.

     

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