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/jci200213462
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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
炎症中的白细胞募集对于宿主防御至关重要，但炎症细胞的过度积累可导致组织损伤。中性粒细胞衍生的丝氨酸蛋白酶（组织蛋白酶G [CG]、中性粒细胞弹性蛋白酶[NE]和蛋白酶3 [PR 3]）在成熟中性粒细胞中特异性表达，并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，我们产生了二肽基肽酶I（DPPI）缺陷的小鼠，并确定DPPI是CG、NE和PR 3完全激活所需的。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，但它们可免受由针对11型胶原的单克隆抗体的被动转移诱导的急性关节炎的影响。具体地，在DPPI-/-小鼠的关节中没有中性粒细胞的积聚。这种保护作用与嗜中性粒细胞衍生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具有相同的抗性。此外，蛋白酶缺陷小鼠对皮下气囊中酵母聚糖和免疫复合物介导的炎症反应降低。这种缺陷伴随着TNF-α和IL-1 β的局部产生减少。这些结果暗示DPPI和多形嗜中性粒细胞衍生的丝氨酸蛋白酶在炎症部位调节细胞因子的产生。
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.