Neutrophil Serine Proteases Promote IL-1β Generation and Injury in Necrotizing Crescentic Glomerulonephritis
Neutrophil Serine Proteases Promote IL-1β Generation and Injury in Necrotizing Crescentic Glomerulonephritis
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DOI：
10.1681/asn.2010080892
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发表时间：
2012-03-01
影响因子：
13.6
通讯作者：
Kettritz, Ralph
中科院分区：
文献类型：
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作者：
Schreiber, Adrian;Pham, Christine T. N.;Kettritz, Ralph
抗中性粒细胞胞浆抗体（ANCA）相关坏死性月牙性GN （NCGN）的发病机制尚不完全清楚。二肽基肽酶I （DPPI）是激活中性粒细胞丝氨酸蛋白酶（NSPs）、组织蛋白酶G、中性粒细胞弹性酶和蛋白酶3所必需的半胱氨酸蛋白酶，它们是调节炎症的酶。我们使用抗髓过氧化物酶（MPO）抗体诱导的NCGN小鼠模型来确定活性NSPs是否参与其发病机制。MPO缺乏的动物用小鼠MPO免疫，照射后移植野生型骨髓，形成NCGN。相比之下，缺乏DPPI或同时缺乏中性粒细胞弹性酶和蛋白酶3的骨髓移植对抗mpo抗体诱导的NCGN小鼠具有保护作用。dppi缺失骨髓重组小鼠肾脏生成的I明显少于野生型骨髓重组小鼠；同样，在体外，dppi缺陷单核细胞对抗mpo抗体的反应产生的IL-1 β明显少于野生型单核细胞。这种IL-1 β的减少依赖于NSP；外源性添加PR3可恢复dppi缺陷单核细胞il - β的产生。最后，il - β受体拮抗剂anakinra保护动物免受抗mpo抗体诱导的NCGN (16.7%+/- 6.0% vs 2.4%+/- 1.7%)，表明IL-1 β在该模型中是一个关键的炎症介质。这些数据表明，抗mpo抗体诱导的NCGN的发展需要nsp依赖性IL-1 β的产生，这些过程可能为人类anca介导的疾病提供治疗靶点。
The pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated necrotizing crescentic GN (NCGN) is incompletely understood. Dipeptidyl peptidase I (DPPI) is a cysteine protease required for the activation of neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase, and proteinase 3, which are enzymes that modulate inflammation. We used a mouse model of anti-myeloperoxidase (MPO) antibody-induced NCGN to determine whether active NSPs contribute to its pathogenesis. MPO-deficient animals immunized with murine MPO, irradiated, and transplanted with wild-type bone marrow developed NCGN. In contrast, transplantation with bone marrow that lacked DPPI or lacked both neutrophil elastase and proteinase 3 protected mice from NCGN induced by anti-MPO antibody. The kidneys of mice reconstituted with DPPI-deficient bone marrow generated significantly less I than did those of mice reconstituted with wild-type bone marrow; similarly, in vitro, DPPI-deficient monocytes produced significantly less IL-1 beta in response to anti-MPO antibody than did wild-type monocytes. This reduction in IL-1 beta was NSP dependent; exogenous addition of PR3 restored IL-beta production in DPPI-deficient monocytes. Last, the IL-beta receptor antagonist anakinra protected animals against anti-MPO antibody-induced NCGN (16.7%+/- 6.0% versus 2.4%+/- 1.7% crescents), suggesting that IL-1 beta is a critical inflammatory mediator in this model. These data suggest that the development of anti-MPO antibody-induced NCGN requires NSP-dependent IL-1 beta generation and that these processes may provide therapeutic targets for ANCA-mediated diseases in humans.