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.)
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.).
Pharmacol Rev. 2016 Jul;68(3):603-30. doi: 10.1124/pr.115.012104.
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.
蛋白酶 3（PR3）在被确定为韦格纳肉芽肿（现称为肉芽肿性多血管炎）中抗中性粒细胞胞质抗体的重要抗原靶点后，引起了科学界的极大关注。尽管在生物合成、储存和细胞外释放过程中中性粒细胞弹性蛋白酶（NE）和 PR3 之间存在许多结构和功能上的相似之处，但近年来的详细研究揭示了它们具有独特的特性和病理生物学功能。高度敏感的 PR3 底物和抑制剂的开发以及 PR3 选择性单敲除小鼠的创建，导致在细胞培养和小鼠模型中鉴定出 PR3 通过激活半胱天冬酶-3诱导细胞死亡的非冗余作用。根据一项针对敲除小鼠的研究，PR3 通过激活半胱天冬酶-3缩短组织中浸润性中性粒细胞的寿命，并加速清除小鼠体内衰老的中性粒细胞。凋亡中性粒细胞上活性人 PR3 的膜暴露重新编程了巨噬细胞对吞噬中性粒细胞的反应，触发促炎细胞因子的分泌，并破坏免疫沉默和组织再生。PR3 诱导的吞噬作用抗炎效应的破坏不仅与多血管炎有关，而且与其他中性粒细胞周转率高的自身免疫性疾病有关。内源性抑制剂（如α-1 蛋白酶抑制剂）对膜结合 PR3 的抑制作用比对 NE 的抑制作用相对较弱，这表明在缺乏α-1 蛋白酶抑制剂的个体中，PR3 活性不受抑制的不良影响比 NE 更早出现。未来，用抗炎工具有效覆盖 PR3 并同时抑制 PR3 和 NE 应该是最有前途的。
