Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis
Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis
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DOI：
10.1172/jci13462
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发表时间：
2002-02-01
影响因子：
15.9
通讯作者：
Pham, CTN
中科院分区：
文献类型：
--
作者：
Adkison, AM;Raptis, SZ;Pham, CTN
炎症中白细胞的募集对于宿主防御至关重要，但炎症细胞的过度积累会导致组织损伤。中性粒细胞来源的丝氨酸蛋白酶（组织蛋白酶 G [CG]、中性粒细胞弹性蛋白酶 [NE] 和蛋白酶 3 [PR3]）在成熟中性粒细胞中特异性表达，被认为在炎症中发挥重要作用。为了研究这些蛋白酶在炎症中的作用，我们培育了一只缺乏二肽基肽酶 I (DPPI) 的小鼠，并确定 DPPI 是 CG、NE 和 PR3 完全激活所必需的。尽管 DPPI-/- 小鼠在无菌性腹膜炎期间具有正常的体外中性粒细胞趋化性和体内中性粒细胞积聚，但它们可以免受针对 11 型胶原单克隆抗体被动转移引起的急性关节炎的影响。具体而言，DPPI-/-小鼠的关节中没有中性粒细胞积聚。这种保护作用与中性粒细胞来源的丝氨酸蛋白酶的失活相关，因为 NE-/- x CG(-/-) 小鼠对抗胶原抗体诱导的关节炎同样具有抵抗力。此外，蛋白酶缺陷的小鼠对皮下气囊中酵母聚糖和免疫复合物介导的炎症的反应降低。这种缺陷伴随着 TNF-α 和 IL-1β 局部产生的减少。这些结果表明 DPPI 和多形核中性粒细胞来源的丝氨酸蛋白酶参与炎症部位细胞因子产生的调节。
Leukocyte recruitment in inflammation is critical for host defense, but excessive accumulation of inflammatory cells can lead to tissue damage. Neutrophil-derived serine proteases (cathepsin G [CG], neutrophil elastase [NE], and proteinase 3 [PR3]) are expressed specifically in mature neutrophils and are thought to play an important role in inflammation. To investigate the role of these proteases in inflammation, we generated a mouse deficient in dipeptidyl peptidase I (DPPI) and established that DPPI is required for the full activation of CG, NE, and PR3. Although DPPI-/- mice have normal in vitro neutrophil chemotaxis and in vivo neutrophil accumulation during sterile peritonitis, they are protected against acute arthritis induced by passive transfer of monoclonal antibodies against type 11 collagen. Specifically, there is no accumulation of neutrophils in the joints of DPPI-/- mice. This protective effect correlates with the inactivation of neutrophil-derived serine proteases, since NE-/- x CG(-/-) mice are equally resistant to arthritis induction by anti-collagen antibodies. In addition, protease-deficient mice have decreased response to zymosan- and immune complex-mediated inflammation in the subcutaneous air pouch. This defect is accompanied by a decrease in local production of TNF-alpha and IL-1beta. These results implicate DPPI and polymorphonuclear neutrophil-derived serine proteases in the regulation of cytokine production at sites of inflammation.