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    Team: Neutrophils and Vasculitis

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    Team leader

    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.

     

    One specific interest of the group of Véronique Witko-Sarsat is the biology of the neutrophils and that 's why with a group of colleagues working on neutrophils, she has created the Neutrophil club at the French Society of Immunology.


    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. Using a proteomic approach, 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 granulomatosis with polyangitis (GPA, formerly called 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).

    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 and this constitute the Research project 2. Our team has recently shown that PR3 can be expressed at the cell surface during apoptosis and that this PR3 can be considered as a danger signal for macrophages and subsequently to plasmacytoid dendritic cells able to polarize CD4T cells towards a profile favoring autoimmunity thus disrupting immune silencing associated with the clearance of apoptotic cells (Video JCI). This ability of PR3 to be both the autoantigen and the endogenous danger signal stimulating the interleukin-1 pathway means that PR3 is indeed THE DOUBLE AGENT in vasculitis (Video : Parisdescartes)

    The research project of the team is aimed at deciphering the molecular and cellular pathways of PR3-driven disturbance. Notably, the project will be focused on the interplay between neutrophils and other innate immune cells including basophils, eosinophils and macrophages (project of Nathalie Thieblemont) as well as innate lymphocytes (project of Benjamin Terrier) using in vitro and in vivo models. Neutrophils are also recognized to modulate adpatative immunity especially via B cells (Project of Luc Mouthon).

    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. Identification of the proteins that are targets of anti-endothelial and anti-vascular smooth muscle cells autoantibodies constitutes the Research project 3 directed by Luc Mouthon.
    The potential pathogenic role of these autoantibodies are studied in other vascular diseases such as Horton disease, arterial pulmonary hypertension ans systemic sclerosis.

    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 Claire Lejeunne 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.

     

    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)

    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 a proteomic study showing that neutrophils from patients with GPA have intrinsic disturbances in programmed cell death pathways and that these disturbances have direct clinical implications.

     

    Recent review articles:

    Chatfield SM, Thieblemont N, Witko-Sarsat V. Expanding Neutrophil  Horizons: New Concepts in Inflammation. J Innate Immun.  2018;10(5-6):422-431.

    Mouasni S, Tourneur L. FADD at the Crossroads between Cancer and  Inflammation.
    Trends Immunol. 2018 Dec;39(12):1036-1053.

    Thieblemont N, Witko-Sarsat V, Ariel A. Regulation of macrophage  activation by proteins expressed on apoptotic neutrophils: Subversion  towards autoimmunity by proteinase 3. Eur J Clin Invest. 2018 Nov;48  Suppl 2:e12990.

    Witko-Sarsat V, Thieblemont N. Granulomatosis with polyangiitis (Wegener
    granulomatosis): A proteinase-3 driven disease? Joint Bone Spine. 2018  Mar;85(2):185-189.

    Marteyn BS, Burgel PR, Meijer L, Witko-Sarsat V. Harnessing  Neutrophil Survival Mechanisms during Chronic Infection by Pseudomonas  aeruginosa: Novel Therapeutic Targets to Dampen Inflammation in Cystic  Fibrosis. Front Cell Infect Microbiol. 2017 Jun 30;7:243.

    Martin KR, Witko-Sarsat V. Proteinase 3: the odd one out that became  an autoantigen. J Leukoc Biol. 2017 Sep;102(3):689-698.

    Witko-Sarsat V and Ohayon D. Proliferating Cell Nuclear Antigen (PCNA) in neutrophil fate. Immunol Reviews. 2016 Sep;273(1):344-56.

    Thieblemont N, Wright HL, Edwards SW, Witko-Sarsat V. Human neutrophils in auto-immunity. Semin Immunol. 2016 Apr;28(2):159-73.

    Chaigne B, Terrier B, Thieblemont N, Witko-Sarsat V, Mouthon L. Dividing the Janus vasculitis? Pathophysiology of eosinophilic granulomatosis with polyangitis. Autoimmun Rev. 2016 Feb;15(2):139-45.

    Original articles:

    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 Mar 4. https://doi.org/10.1016/j.kint.2019.02.017

    Alkan M, Sayes F, Ramadan A, Machavoine F, Dy M, Schneider E and Thieblemont N. Basophil activation through TLR2 and TLR4 signaling pathways. AIMS Allergy and Immunology. 2018 Aug 6; 2(3):126–40.

    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 Feb 25;10(3):190.

    Tacnet-Delorme P, Gabillet J, Chatfield S, Thieblemont N, Frachet P,  Witko-Sarsat V. Proteinase 3 Interferes With C1q-Mediated Clearance of  Apoptotic Cells. Front Immunol. 2018 Apr 25;9:818.

    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 (Oxford). 2018 Jun 1;57(6):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. J  Immunol. 2017 Dec 1;199(11):3914-3924.

    Régent A, Ly KH, Groh M, Khifer C, Lofek S, Clary G, Chafey P, Baud  V, Broussard C, Federici C, Labrousse F, Mesturoux L, Le Jeunne C,  Vidal E, Brezin A, Witko-Sarsat V, Guillevin L, Mouthon L. Molecular  analysis of vascular smooth muscle cells from patients with giant cell  arteritis: Targeting endothelin-1 receptor to control proliferation.  Autoimmun Rev. 2017 Apr;16(4):398-406.

    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,  Witko-Sarsat V. Cytoplasmic proliferating cell nuclear antigen  connects glycolysis and cell survival in acute myeloid leukemia. Sci  Rep. 2016 Oct 19;6:35561.

    Monceaux V, Chiche-Lapierre C, Chaput C, Witko-Sarsat V, Prevost MC,  Taylor CT, Ungeheuer MN, Sansonetti PJ, Marteyn BS. Anoxia and glucose  supplementation preserve neutrophil viability and function. Blood.  2016 Aug 18;128(7):993-1002.

    Martin KR, Kantari-Mimoun C, Yin M, Pederzoli-Ribeil M, Angelot-Delettre F, Ceroi A, Grauffel C, Benhamou M, Reuter N, Saas P, Frachet P, Boulanger CM, Witko-Sarsat V. Proteinase 3 Is a Phosphatidylserine-binding Protein That Affects the Production and Function of Microvesicles. J Biol Chem. 2016 May 13;291(20):10476-89.
    WEB News Cochin Institute

    Martin C, Ohayon D, Alkan M, Mocek J, Pederzoli-Ribeil M, Candalh C, Thevenot G, Millet A, Tamassia N, Cassatella MA, Thieblemont N, Burgel PR, Witko-Sarsat V.Neutrophil-expressed p21/waf1 Favors Inflammation Resolution in Pseudomonas aeruginosa Infection.
    Am J Respir Cell Mol Biol. 2016 May;54(5):740-50.

    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 Nov 2;125(11):4107-21.*equal contribution

    De Chiara A, Pederzoli-Ribeil M, Mocek J, Candalh C, Mayeux P, Millet A, Witko-Sarsat V Characterization of cytosolic proliferating cell nuclear antigen (PCNA) in neutrophils: antiapoptotic role of the monomer. J Leukoc Biol. 2013 99:723-731

    Dib H, Chafey P, Clary G, Federici C, Le Gall M, Dwyer J, Gavard J, Tamas N, Bussone G, Broussard C, Camoin L, Witko-Sarsat V, Tamby MC, Mouthon L. Proteomes of umbilical vein and microvascular endothelial cells reflect distinct biological properties and influence immune recognition.  Proteomics. 2012 Aug;12(15-16):2547-55.

    Bussone G, Tamby MC, Calzas C, Kherbeck N, Sahbatou Y, Sanson C, Ghazal K, Dib H, Weksler BB, Broussard C, Verrecchia F, Yaici A, Witko-Sarsat V, Simonneau G, Guillevin L, Humbert M, Mouthon L. IgG from patients with pulmonary arterial hypertension and/or systemic sclerosis binds to vascular smooth muscle cells and induces cell contraction.  Ann Rheum Dis. 2012 Apr;71(4):596-605.

    Bouayad D, Pederzoli-Ribeil M, Mocek J, Candalh C, Arlet JB, Hermine O, Reuter N, Davezac N, Witko-Sarsat VNuclear-to-cytoplasmic relocalization of the proliferating cell nuclear antigen (PCNA) during differentiation involves a chromosome region maintenance 1 (CRM1)-dependent export and is a prerequisite for PCNA antiapoptotic activity in mature neutrophils. J Biol Chem. 2012 Sep 28;287(40):33812-25.

    Gabillet J, Millet A, Pederzoli-Ribeil M, Tacnet-Delorme P, Guillevin L, Mouthon L, Frachet P, Witko-Sarsat VProteinase 3, the autoantigen in granulomatosis with polyangiitis, associates with calreticulin on apoptotic neutrophils, impairs macrophage phagocytosis, and promotes inflammation. J Immunol. 2012 Sep 1;189(5):2574-83.

    Witko-Sarsat V, Mocek J, Bouayad D, Tamassia N, Ribeil JA, Candalh 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 Nov 22;207(12):2631-45.

     

     

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