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    The crucial role of neutrophils becomes clearer in granulomatosis with polyangiitis

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    The crucial role of neutrophils becomes clearer in granulomatosis with polyangiitis: identification of potential therapeutic targets by proteomics

    Granulomatosis with polyangitiis (GPA) is a vasculitis characterized by vessel inflammation affecting both lung and kidney. This systemic disease can be lethal if left untreated. Polymorphonuclear neutrophils are major actors of GPA because they are responsible for the necrosis of small vessels. The team of Véronique Witko-Sarsat in collaboration with the Department of Internal Medicine in Cochin hospital and with the National Reference Center for Vasculitis and Systemic Sclerosis directed by Luc Mouthon, has provided evidence that the proteome of neutrophils from untreated patients at diagnosis was significantly different from healthy controls and from patients in remission. Several proteins involved in the recognition of apoptotic neutrophils to allow their elimination by macrophages from the inflammatory site are dysregulated thereby resulting in unabated inflammation. Harnessing these dysregulated pathways could lead to novel therapeutic opportunities to treat vasculitis. 

    This translational study carried out in collaboration with the proteomic facility of Institut Cochin/ U. Paris Descartes 3P5 is published in Kidney International.

     

    Polymorphonuclear neutrophils are major actors of granulomatosis with polyangiitis (GPA) which is a vasculitis characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Neutrophils are key players in GPA as the majority of patients have ANCA directed against proteinase 3 (PR3). It is known that the persistence of activated neutrophils at the site of inflammation results in vascular necrosis of small vessels but the molecular mechanisms are still unknown.

    The aim of the national clinical research program “PHRC-NEUTROVASC” was to test whether neutrophils could serve as markers of disease evolution and to identify potential intrinsic abnormalities in neutrophils from GPA patients. Taking advantages of patient cohorts from the National Reference Center for Vasculitis and Systemic Sclerosis, the team of Véronique Witko-Sarsat has provided evidence for the first time that the proteome of neutrophils from patients was significantly different from healthy controls. This study has also shown that neutrophil activation was different between the relapse (before treatment) and remission. These differences were exacerbated after apoptosis thereby demonstrating that the death pathways were disturbed in neutrophils from patients during active disease but were partially normalized after treatment. 

    Identification by mass spectrometry of « pathologic » proteins (especially annexin-A1 and calreticulin), involved in the recognition of apoptotic neutrophils by macrophages to allow their elimination from the inflammatory site, shed some light on the mechanisms involved in the defect in the resolution of inflammation and vascular necrosis observed in GPA patients. Interestingly, in neutrophils from patients with renal involvement, these proteins are assembled in a membrane complex associated with the phospholipidscramblase 1 and to the autoantigen PR3 and could serve a biomarker of disease activity.

    This work has shown for the first time that GPA is associated with a profound dysregulation of death pathways in neutrophils. The expression the autoantigen PR3 and its partner proteins are crucial pathogenic determinants in the persistence of inflammation and in the pathophysiology of GPA. 

    This clinical study together with the proteomic analysis of neutrophils is a very unique resource and should allow to identify new therapeutic targets. Current treatment strategies based on corticosteroids and immunosuppressive drugs allow remission with a high risk of relapses and serious adverse effects. This study also emphasizes the necessity to develop strategies aimed at regulating neutrophils to block the mechanisms that induce the disease to propose curative treatments which are currently lacking.

     

    Figure legend

    Neutrophils from GPA patients have an intrinsic dysregulation in proteins involved in death pathways and in mechanisms of recognition of apoptotic neutrophils by macrophages. This disturbance could contribute to the unabated inflammation and the destruction of blood vessels by activated neutrophils.

     

    Reference 

    Proteomic analysis of neutrophils in ANCA-associated vasculitis reveals a dysregulation in proteinase 3-associated proteins such as annexin-A1involved in apoptotic cell clearance Judith Everts-Graber, Katherine R. Martin, Nathalie Thieblemont, Julie Mocek, Arnaud Roccabianca, Philippe Chafey, Morgane Le Gall, Pascale Tacnet-Delorme, Chris P. Reutelingsperger, Jean-Marc Naccache, Bernard Bonnotte, Alexandre Karras, Xavier Puéchal, Loïc Guillevin, Benjamin Terrier, Philippe Frachet, Mauro Perretti, Luc Mouthonand Véronique Witko-Sarsat. Kidney International (2019) 96, 397–408. 

     

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