Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin
Proteinase 3 and neutrophil elastase enhance inflammation in mice by inactivating antiinflammatory progranulin
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DOI：
10.1172/jci34694
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发表时间：
2008-07-01
影响因子：
15.9
通讯作者：
Jenne, Dieter E.
中科院分区：
文献类型：
--
作者：
Kessenbrock, Kai;Froehlich, Leopold;Jenne, Dieter E.
中性粒细胞形成了人体的第一道抗菌防线，但它们也会导致组织损伤和非感染性慢性炎症。蛋白酶3（PR3）和中性粒细胞。弹性蛋白酶（NE）是两种丰富的中性粒细胞丝氨酸蛋白酶，具有重叠和潜在冗余的底物特异性，涉及抗菌防御。在这里，我们揭示了PR3和NE在体内中性粒细胞活化和非感染性炎症中的合作作用，我们认为这是新颖的。缺乏PR3和NE的小鼠在体内表现出强烈减少的免疫复合物介导的（IC介导的）中性粒细胞浸润，以及在体外减少IC对分离的中性粒细胞的激活。相反，在仅缺乏NE的小鼠中，中性粒细胞向IC的募集仅轻微受损。缺乏PR3和NE的小鼠的缺陷与PGRN的积累直接相关。PR3和NE都在体外和体内中性粒细胞活化和炎症期间切割PGRN。重组PGRN的局部给药有效地抑制了体内嗜酸性炎症，表明PGRN是一种重要的炎症抑制介质。我们得出结论，PR3和NE通过消除PGRN的局部炎症活性来增强嗜中性粒细胞依赖性炎症。我们的研究结果支持使用丝氨酸蛋白酶抑制剂作为抗肿瘤剂。
Neutrophil granulocytes form the body's first line of antibacterial defense, but they also contribute to tissue injury and noninfectious, chronic inflammation. Proteinase 3 (PR3) and neutrophil. elastase (NE) are 2 abundant neutrophil serine proteases implicated in antimicrobial defense with overlapping and potentially redundant substrate specificity. Here, we unraveled a cooperative role for PR3 and NE in neutrophil activation and noninfectious inflammation in vivo, which we believe to be novel. Mice lacking both PR3 and NE demonstrated strongly diminished immune complex-mediated (IC-mediated) neutrophil infiltration in vivo as well as reduced activation of isolated neutrophils by ICs in vitro. In contrast, in mice lacking just NE, neutrophil recruitment to ICs was only marginally impaired. The defects in mice lacking both PR3 and NE were directly linked to the accumulation of antiinflammatory progranulin (PGRN). Both PR3 and NE cleaved PGRN in vitro and during neutrophil activation and inflammation in vivo. Local administration of recombinant PGRN potently inhibited neutrophilic inflammation in vivo, demonstrating that PGRN represents a crucial inflammation-suppressing mediator. We conclude that PR3 and NE enhance neutrophil-dependent inflammation by eliminating the local antiinflammatory activity of PGRN. Our results support the use of serine protease inhibitors as antiinflammatory agents.