Opsonization of apoptotic neutrophils by anti-neutrophil cytoplasmic antibodies (ANCA) leads to enhanced uptake by macrophages and increased release of tumour necrosis factor-alpha (TNF-alpha).
Since proteinase 3 (PR3)-ANCA interact with PR3 on the surface of apoptotic polymorphonuclear neutrophils (PMN) and ingestion of apoptotic PMN is known to modulate macrophage inflammatory reactions, we raised the question whether PR3-ANCA-opsonized apoptotic PMN influence the uptake by macrophages and their state of activation. We therefore analysed the effects of PR3-ANCA-opsonized apoptotic PMN on the uptake process by enzymatic assay. We further investigated the production of TNF-alpha, IL-10, IL-12 and the secretion of lipid inflammatory mediators (TxB2, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2)) by human monocyte-derived macrophages using FACS and ELISA methods. We show that PMN-opsonization by PR3-ANCA substantially enhances phagocytosis by macrophages and thereby triggers the production of TNF-alpha and TxB2. These in vitro findings indicate that PR3-ANCA opsonization of apoptotic PMN might be an important mechanism in the pathogenesis of Wegener's granulomatosis (WG), prompting macrophages to produce proinflammatory mediators. These mediators, mainly TNF-alpha, might prime further PMN leading to perpetuation of the known priming-dependent mechanisms of ANCA action.
Moosig
F
F
Department of Rheumatology, University of Lübeck, Lübeck and Rheumaklinik Bad Bramstedt, Bad Bramstedt, Germany.
Csernok
E
E
Kumanovics
G
G
Gross
W L
WL
D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D017209:Apoptosis / Q000276:immunology*; D015232:Dinoprostone / Q000378:metabolism; D014890:Granulomatosis with Polyangiitis / Q000097:blood / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007975:Leukotriene B4 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D053146:Myeloblastin; D009504:Neutrophils / Q000276:immunology*; D009895:Opsonin Proteins / Q000276:immunology*; D010587:Phagocytosis / Q000276:immunology*; D012697:Serine Endopeptidases / Q000276:immunology*; D013929:Thromboxane B2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D019268:Antibodies, Antineutrophil Cytoplasmic; D009895:Opsonin Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D007975:Leukotriene B4; D013929:Thromboxane B2; D012697:Serine Endopeptidases; D053146:Myeloblastin; D015232:Dinoprostone