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.

中文翻译：

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靶向人类疾病中性粒细胞蛋白酶3的潜在抗炎治疗药物抑制剂和抗体片段。

蛋白酶3（PR3）被鉴定为韦格纳肉芽肿病（现称为多血管炎肉芽肿病）中抗中性粒细胞胞浆抗体的重要抗原靶标后，受到了极大的科学关注。尽管在生物合成，储存和细胞外释放过程中嗜中性粒细胞弹性蛋白酶（NE）和PR3之间在结构和功能上有许多相似之处，但近年来的详细研究已经显示出独特的特性和病理生物学功能。人类PR3的高度敏感的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通过细胞培养和小鼠模型中procaspase-3激活来鉴定PR3在细胞死亡诱导中的非冗余作用。根据对基因剔除小鼠的研究，PR3缩短了浸润性嗜中性粒细胞在组织中的寿命，并加速了小鼠中老年嗜中性粒细胞的清除。活跃的人PR3在凋亡中性粒细胞上的膜暴露可重编程巨噬细胞对吞噬性中性粒细胞的反应，触发促炎性细胞因子的分泌，并破坏免疫沉默和组织再生。PR3引起的胞吐抗炎作用的破坏可能不仅与肉芽肿合并多血管炎有关，而且与中性粒细胞更新率高的其他自身免疫性疾病有关。内源性抑制剂（例如α-1-蛋白酶抑制剂）对膜结合PR3的抑制作用要弱于NE，这表明在患有α-1-蛋白酶抑制剂的个体中，无抵抗的PR3活性的不良反应要比NE早出现。不足。