On the Origin of Surface Proteinase 3 of Nonmyeloid Cells: Evidence Favoring an Exogenous Source

Zhou, Zhijie; Dionne, Annie; Richard, C A; Ménard, Henri A.

doi:10.1006/clim.2000.4922

Cited by 6 publications

(5 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ANCA target antigens released from activated or dying neutrophils can also bind directly to endothelial cells [134]. This may result in apoptosis of endothelial cells and in localized immune complex formation with circulating ANCA [135].…”

Section: Role Of B and T Lymphocytesmentioning

confidence: 99%

Pathogenesis of ANCA-Associated Vasculitis

2012

View full text Add to dashboard Cite

Antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides (AAV) are a group of systemic vasculitis syndromes characterized by inflammation and necrosis of blood vessel walls. Genetic, epigenetic, and environmental factors contribute to the etiology and pathogenesis of AAV. On the basis of currently available clinical and experimental evidence, it is reasonable to believe that, in predisposed patients, different triggers can lead to the production of autoantibodies (ANCA) that, in the context of an inflammatory environment, can cause tissue inflammation and vascular injury. Several different pathways and mechanisms in the pathogenesis of AAV are described in this contemporary review.

show abstract

Section: Role Of B and T Lymphocytesmentioning

confidence: 99%

Pathogenesis of ANCA-Associated Vasculitis

2012

View full text Add to dashboard Cite

show abstract

“…The fact that p21 is a molecular target of PR3 could have special relevance in mature neutrophils in which PR3 is reexpressed following TNF-␣ treatment (6) and in vivo during the inflammatory process (7). Immunoperoxidase labeling showed 10.…”

Section: Effect Of Tnf-␣ On the Expression Of P21 In Mature Neutrophilsmentioning

confidence: 99%

“…First, the subcellular localization of PR3 is not restricted to the azurophil granule compartment, but its membrane-associated form is also localized in secretory vesicles, thus leading to plasma membrane expression upon very mild neutrophil stimulation (5). Second, in contrast to all other proteins from azurophil granules whose biosynthesis is restricted to the promyelocytic stage, PR3 mRNA is re-expressed in vitro in both mature neutrophils and monocytes after tumor necrosis factor-␣ (TNF-␣) stimulation (6). Moreover, we recently demonstrated that PR3 biosynthesis is induced in vivo in monocytes from children with cystic fibrosis only during episodes of acute pulmonary inflammation (7).…”

mentioning

confidence: 99%

Cleavage of p21 by Proteinase-3, a Myeloid-specific Serine Protease, Potentiates Cell Proliferation

Witko‐Sarsat

Canteloup

Durant

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

In this study, we present evidence for the critical role of proteinase-3 (PR3) in the proliferation of myeloid cells via the proteolytic regulation of the cyclin-dependent kinase inhibitor p21 waf1 . Expression of recombinant PR3 in rat (RBL) or human (HMC1) mast cell lines increased bromodeoxyuridine incorporation and CDK2 activity compared with RBL and HMC1 cells transfected with an enzymatically inactive PR3 mutant (PR3(S203A)) or with human neutrophil elastase. Western blot analysis of p21 waf1 showed an absence of detectable protein, despite normal levels of p21 mRNA. Ectopic overexpression of p21 restored normal levels of p21 in the RBL/PR3/p21 double transfectants and reverted the proliferative effect of PR3. Inhibition of the 26 S proteasome by lactacystin or of caspases by benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone did not inhibit p21 proteolysis. p21 cleavage correlated with PR3 expression in HMC1 cells infected with recombinant adenoviral vector Ad/PR3. During in vitro studies, purified p21 was cleaved by PR3, resulting in a 10-kDa p21 fragment. Employing double immunofluorescence confocal microscopy, subcellular fractionation, and coimmunoprecipitation, we found that PR3 and p21 colocalized in the cytosol. In human neutrophils treated with tumor necrosis factor-␣, which induces PR3 reexpression, we observed that p21 disappeared and was reversed by Pefabloc, a serine proteinase inhibitor. The physiopathological implications of the cleavage of p21 by PR3 have to be determined.Myeloid cells express several lineage-specific proteinases in the course of their differentiation and store them in granular pools. As a result, mature phagocytes are equipped with a large assortment of proteinases that play a key role in the noxious potential to pathogens or host tissues (1, 2). We hypothesized that a redundancy in serine proteinase activities might be important for mediating various regulatory functions in myeloid cell differentiation as well as in mature phagocytes, including, but not restricted to, microbicidal activity. We also assumed that each serine proteinase could have a unique substrate specificity. Proteinase-3 (PR3) 1 and human neutrophil elastase (HNE) belong to the myeloid serine proteinase family, which also includes cathepsin G and azurocidin, which are implicated in the destruction of microorganisms and extracellular matrix degradation (3). Although PR3 shares the highest sequence homology with HNE (60%) and has a similar substrate specificity, PR3 has some very special properties that are distinct from those of HNE (4). First, the subcellular localization of PR3 is not restricted to the azurophil granule compartment, but its membrane-associated form is also localized in secretory vesicles, thus leading to plasma membrane expression upon very mild neutrophil stimulation (5). Second, in contrast to all other proteins from azurophil granules whose biosynthesis is restricted to the promyelocytic stage, PR3 mRNA is re-expressed in vitro in both mature neutrophils and monocytes after tumor necr...

show abstract

“…89 ROS can be directly damaging to surrounding cells (including vascular endothelial cells) and/or oxidize cells and cell components that alter a range of immune functions. 90 Released MPO and PR3 may bind to endothelial cells, for example, via charge interaction 91,92 or, for PR3, via protease activated receptors (PARs). 93 While one study suggests that PR3-PAR2 interaction enhances vascular integrity, 93 other reports suggest that MPO and PR3 promote endothelial cell cytotoxicity 94 and vascular damage potentially through engagement of ANCA and/or activated leukocytes.…”

Section: Anca-mediated Immune Cell Activationmentioning

confidence: 99%

Anti-neutrophil cytoplasmic antibodies (ANCA): Antigen interactions and downstream effects

Sundqvist

Gibson

Bowers

et al. 2020

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Neutrophils are the most abundant leukocytes in circulation and are key "first responders" in the immune response to infectious and non-infectious stimuli. Unlike other immune cells, neutrophils can mount a robust response (including a change in surface markers and the production of extracellular traps and reactive oxygen species) just minutes after sensing a disturbance. It has been speculated that, in some individuals, the activation of neutrophils inadvertently leads to the generation of anti-neutrophil cytoplasmic autoantibodies (ANCA) against particular neutrophil proteins (antigens) such as myeloperoxidase (MPO) and proteinase 3 (PR3). In these individuals, continuous ANCA-antigen interactions are thought to drive persistent activation of neutrophils, chronic immune activation, and disease, most notably, small vessel vasculitis. There are significant gaps however in our understanding of the underlying mechanisms and even the pathogenicity of ANCA given that vasculitis can develop in the absence of ANCA, and that ANCA have been found in circulation in other conditions with no apparent contribution to disease. These gaps are particularly evident in the context of human studies. Herein, we review knowledge on neutrophil-derived ANCA antigens PR3 and MPO, ANCA generation, and ANCA-antigen interaction(s) that may promote immune activation and disease.

show abstract

On the Origin of Surface Proteinase 3 of Nonmyeloid Cells: Evidence Favoring an Exogenous Source

Cited by 6 publications

References 39 publications

Pathogenesis of ANCA-Associated Vasculitis

Pathogenesis of ANCA-Associated Vasculitis

Cleavage of p21 by Proteinase-3, a Myeloid-specific Serine Protease, Potentiates Cell Proliferation

Anti-neutrophil cytoplasmic antibodies (ANCA): Antigen interactions and downstream effects

Contact Info

Product

Resources

About