Proteinase 3, the Autoantigen in Granulomatosis with Polyangiitis, Associates with Calreticulin on Apoptotic Neutrophils, Impairs Macrophage Phagocytosis, and Promotes Inflammation
| Autor: | Luc Mouthon, Arnaud Millet, Philippe Frachet, Julie Gabillet, Pascale Tacnet-Delorme, Loïc Guillevin, Véronique Witko-Sarsat, Magali Pederzoli-Ribeil |
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| Rok vydání: | 2012 |
| Předmět: |
Neutrophils
Myeloblastin Phagocytosis Immunology Microscopic Polyangiitis Apoptosis Inflammation Biology medicine.disease_cause Autoantigens Proinflammatory cytokine Autoimmunity Mice Adjuvants Immunologic Proteinase 3 medicine Animals Humans Immunology and Allergy cardiovascular diseases Macrophages Granulomatosis with Polyangiitis Membrane Proteins medicine.disease Rats Cell biology Mice Inbred C57BL Macrophages Peritoneal biology.protein medicine.symptom Calreticulin Granulomatosis with polyangiitis |
| Zdroj: | The Journal of Immunology. 189:2574-2583 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Proteinase 3 (PR3) is the target of anti-neutrophil cytoplasm Abs in granulomatosis with polyangiitis, a form of systemic vasculitis. Upon neutrophil apoptosis, PR3 is coexternalized with phosphatidylserine and impaired macrophage phagocytosis. Calreticulin (CRT), a protein involved in apoptotic cell recognition, was found to be a new PR3 partner coexpressed with PR3 on the neutrophil plasma membrane during apoptosis, but not after degranulation. The association between PR3 and CRT was demonstrated in neutrophils by confocal microscopy and coimmunoprecipitation. Evidence for a direct interaction between PR3 and the globular domain of CRT, but not with its P domain, was provided by surface plasmon resonance spectroscopy. Phagocytosis of apoptotic neutrophils from healthy donors was decreased after blocking lipoprotein receptor-related protein (LRP), a CRT receptor on macrophages. In contrast, neutrophils from patients with granulomatosis with polyangiitis expressing high membrane PR3 levels showed a lower rate of phagocytosis than those from healthy controls not affected by anti-LRP, suggesting that the LRP-CRT pathway was disturbed by PR3-CRT association. Moreover, phagocytosis of apoptotic PR3-expressing cells potentiated proinflammatory cytokine in vitro by human monocyte-derived macrophages and in vivo by resident murine peritoneal macrophages, and diverted the anti-inflammatory response triggered by the phagocytosis of apoptotic cells after LPS challenge in thioglycolate-elicited murine macrophages. Therefore, membrane PR3 expressed on apoptotic neutrophils might amplify inflammation and promote autoimmunity by affecting the anti-inflammatory “reprogramming” of macrophages. |
| Databáze: | OpenAIRE |
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