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Pharmacol Rev. 2016 Jul;68(3):603-30. doi: 10.1124/pr.115.012104.

Inhibitors and Antibody Fragments as Potential Anti-Inflammatory Therapeutics Targeting Neutrophil Proteinase 3 in Human Disease.

Author information

1
INSERM U-1100, Centre d'Etude des Pathologies Respiratoires and Université François Rabelais, Tours, France (B.K., C.G., F.G.); Faculty of Chemistry, University of Gdansk, Gdansk, Poland (A.L., M.W.); Architecture et Fonction des Macromolécules Biologiques, Unité Mixte de Recherche 7257, Marseille, France (C.K.); Génétique, Immunothérapie, Chimie et Cancer, Unité Mixte de Recherche 7292, Université François Rabelais, Tours, France (H.W.); Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic and Foundation, Rochester, Minnesota (U.S.); Comprehensive Pneumology Center, Institute of Lung Biology and Disease, German Center for Lung Research, Munich, Germany (D.E.J.); and Max Planck Institute of Neurobiology, Planegg-Martinsried, Germany (D.E.J.) brice.korkmaz@inserm.fr.
2
INSERM U-1100, Centre d'Etude des Pathologies Respiratoires and Université François Rabelais, Tours, France (B.K., C.G., F.G.); Faculty of Chemistry, University of Gdansk, Gdansk, Poland (A.L., M.W.); Architecture et Fonction des Macromolécules Biologiques, Unité Mixte de Recherche 7257, Marseille, France (C.K.); Génétique, Immunothérapie, Chimie et Cancer, Unité Mixte de Recherche 7292, Université François Rabelais, Tours, France (H.W.); Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic and Foundation, Rochester, Minnesota (U.S.); Comprehensive Pneumology Center, Institute of Lung Biology and Disease, German Center for Lung Research, Munich, Germany (D.E.J.); and Max Planck Institute of Neurobiology, Planegg-Martinsried, Germany (D.E.J.).

Abstract

Proteinase 3 (PR3) has received great scientific attention after its identification as the essential antigenic target of antineutrophil cytoplasm antibodies in Wegener's granulomatosis (now called granulomatosis with polyangiitis). Despite many structural and functional similarities between neutrophil elastase (NE) and PR3 during biosynthesis, storage, and extracellular release, unique properties and pathobiological functions have emerged from detailed studies in recent years. The development of highly sensitive substrates and inhibitors of human PR3 and the creation of PR3-selective single knockout mice led to the identification of nonredundant roles of PR3 in cell death induction via procaspase-3 activation in cell cultures and in mouse models. According to a study in knockout mice, PR3 shortens the lifespan of infiltrating neutrophils in tissues and accelerates the clearance of aged neutrophils in mice. Membrane exposure of active human PR3 on apoptotic neutrophils reprograms the response of macrophages to phagocytosed neutrophils, triggers secretion of proinflammatory cytokines, and undermines immune silencing and tissue regeneration. PR3-induced disruption of the anti-inflammatory effect of efferocytosis may be relevant for not only granulomatosis with polyangiitis but also for other autoimmune diseases with high neutrophil turnover. Inhibition of membrane-bound PR3 by endogenous inhibitors such as the α-1-protease inhibitor is comparatively weaker than that of NE, suggesting that the adverse effects of unopposed PR3 activity resurface earlier than those of NE in individuals with α-1-protease inhibitor deficiency. Effective coverage of PR3 by anti-inflammatory tools and simultaneous inhibition of both PR3 and NE should be most promising in the future.

PMID:
27329045
DOI:
10.1124/pr.115.012104
[Indexed for MEDLINE]

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