NDLI: Proteinase 3, the autoantigen in granulomatosis with polyangiitis, associates with calreticulin on apoptotic neutrophils, impairs macrophage phagocytosis, and promotes inflammation.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Guillevin, Loïc Frachet, Philippe Witko-Sarsat, Véronique Gabillet, Julie Pederzoli-Ribeil, Magali Tacnet-Delorme, Pascale Mouthon, Luc Millet, Arnaud
Description	Country affiliation: France Author Affiliation: Gabillet J ( INSERM U1016, Paris 75014, France.)
Abstract	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.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	5
Volume Number	189
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2012-09-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Apoptosis Immunology Autoantigens Metabolism Calreticulin Granulomatosis With Polyangiitis Macrophages Microscopic Polyangiitis Myeloblastin Neutrophils Adjuvants, Immunologic Physiology Animals Enzymology Pathology Inflammation Macrophages, Peritoneal Membrane Proteins Mice Mice, Inbred C57bl Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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