title: Proteinase 3 on apoptotic cells disrupts immune silencing in autoimmune vasculitis.
abstract: Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Millet
authors.forename: Katherine R
authors.initials: KR
authors.lastname: Martin
authors.forename: Francis
authors.initials: F
authors.lastname: Bonnefoy
authors.forename: Philippe
authors.initials: P
authors.lastname: Saas
authors.forename: Julie
authors.initials: J
authors.lastname: Mocek
authors.forename: Manal
authors.initials: M
authors.lastname: Alkan
authors.forename: Benjamin
authors.initials: B
authors.lastname: Terrier
authors.forename: Anja
authors.initials: A
authors.lastname: Kerstein
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
authors.forename: Senthil Kumaran
authors.initials: SK
authors.lastname: Satyanarayanan
authors.forename: Amiram
authors.initials: A
authors.lastname: Ariel
authors.forename: Jean-Antoine
authors.initials: JA
authors.lastname: Ribeil
authors.forename: Loïc
authors.initials: L
authors.lastname: Guillevin
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cassatella
authors.forename: Antje
authors.initials: A
authors.lastname: Mueller
authors.forename: Nathalie
authors.initials: N
authors.lastname: Thieblemont
authors.forename: Peter
authors.initials: P
authors.lastname: Lamprecht
authors.forename: Luc
authors.initials: L
authors.lastname: Mouthon
authors.forename: Sylvain
authors.initials: S
authors.lastname: Perruche
authors.forename: Véronique
authors.initials: V
authors.lastname: Witko-Sarsat
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology; D017209:Apoptosis / Q000502:physiology*; D001324:Autoantigens / Q000276:immunology / Q000502:physiology*; D002462:Cell Membrane / Q000201:enzymology; D060833:Cellular Microenvironment; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D014890:Granulomatosis with Polyangiitis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008168:Lung / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053146:Myeloblastin / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology; D010538:Peritonitis / Q000276:immunology / Q000473:pathology; D010587:Phagocytosis; D053573:Receptors, Interleukin-1 Type I / Q000502:physiology; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D001324:Autoantigens; D016207:Cytokines; C583355:IL1R1 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; D016179:Granulocyte Colony-Stimulating Factor; D009569:Nitric Oxide; D053146:Myeloblastin