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Rôle pro-inflammatoire et immunomodulateur de la proteinase 3 membranaire exprimée au cours de l'apoptose : implications dans la granulomatose avec polyangéite

Abstract : Granulomatosis with polyangiitis is a systemic vasculitides associated with an autoimmune response directed against proteinase 3 a neutrophil-derived serine protease. This protein presents a very specific pattern of expression in neutrophils, illustrated by its membrane expression during apoptosis. The ability of PR3 to bind membrane is based on the existence of four amino-acids involved in the formation of a hydrophobic patch. The membrane expression during apoptosis, which is dependent of the existence of the hydrophobic patch, leads to an interaction between proteinase 3 and calreticulin, a “eat-me” signal involved in the recognition of apopotic cells by macrophages. As a consequence, we have found that proteinase 3 expressed at the surface of apoptotic cells hampers the normal anti-inflammatory phenotype of macrophages following phagocytosis of apoptotic cells. The pro-inflammatory phenotype resulting from proteinase 3 expressing cells phagocytosis by macrophages is a MyD88 signaling pathway dependant mechanism mimicking an alarmin stimulation. This activation of macrophages through the secretion of chemokines (MCP-1, KC, MIP-1α and MIP-1β) implicated in the recruitment of cells expressing proteinase 3 participate in the maintenance of inflammation. This macrophage-induced microenvironment was also found to impact the immune silencing of apoptotic cells clearance by plasmacytoid dendritic cell-dependant T cell interaction leading to a skewed Th2/Th9 T cell distribution instead of the generation of regulatory T cells. Proteinase 3, which is encoded by a G-CSF responsive gene, was also able to recruit more over expressing proteinase 3 cells by its ability to stimulate G-CSF secretion. Then proteinase 3 through its corruption of inflammation resolving mechanisms and its self-induced over expression appears to be a central key in the physiopathology of granulomatosis with polyangiitis.
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Submitted on : Monday, February 3, 2014 - 10:37:10 AM
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  • HAL Id : tel-00940917, version 1

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Arnaud Millet. Rôle pro-inflammatoire et immunomodulateur de la proteinase 3 membranaire exprimée au cours de l'apoptose : implications dans la granulomatose avec polyangéite. Médecine humaine et pathologie. Université René Descartes - Paris V, 2014. Français. ⟨NNT : 2014PA05S001⟩. ⟨tel-00940917⟩

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