Cathepsin G and Neutrophil Elastase Contribute to Lung-Protective Immunity against Mycobacterial Infections in Mice
Cathepsin G and Neutrophil Elastase Contribute to Lung-Protective Immunity against Mycobacterial Infections in Mice
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DOI：
10.4049/jimmunol.1103346
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发表时间：
2012-05-01
影响因子：
4.4
通讯作者：
Maus, Ulrich A.
中科院分区：
文献类型：
--
作者：
Steinwede, Kathrin;Maus, Regina;Maus, Ulrich A.
中性粒细胞丝氨酸蛋白酶组织蛋白酶G（CG）和中性粒细胞弹性蛋白酶（NE）参与免疫调节过程，并对各种病原体发挥抗菌活性。迄今为止，它们在肺宿主防御分枝杆菌感染中的作用和治疗潜力尚不清楚。本文研究了CG和NE在肺组织对卡介苗（BCG）耐药中的作用。CG-缺陷小鼠和甚至更明显的CG/NE-缺陷小鼠表现出对M.牛BCG与野生型小鼠相比。此外，肉芽肿形成更明显的M。牛BCG感染的CG/NE缺陷型小鼠与CG缺陷型和野生型小鼠相比。对专业吞噬细胞亚群的仔细检查显示，只有中性粒细胞将CG和NE穿梭进入M的支气管肺泡腔。Bovis BCG感染的小鼠。因此，具有CG/NE缺陷型造血系统的嵌合野生型小鼠在对M.牛卡介苗感染。治疗应用的人CG/NE封装在脂质体中，与肺泡巨噬细胞中的分枝杆菌共定位，通过激光扫描和电子显微镜进行评估。重要的是，用CG/NE负载的脂质体治疗显著降低了小鼠肺中的分枝杆菌负荷。总之，嗜中性粒细胞衍生的CG和NE在抗分枝杆菌反应的早期阶段对病原体复制的减速起关键作用。此外，据我们所知，我们首次表明脂质体包裹的CG/NE对肺部分枝杆菌感染具有治疗潜力。这些发现可能与人类结核病治疗的新辅助方法有关。免疫学杂志，2012，188：4476-4487。
The neutrophil serine proteases cathepsin G (CG) and neutrophil elastase (NE) are involved in immune-regulatory processes and exert antibacterial activity against various pathogens. To date, their role and their therapeutic potential in pulmonary host defense against mycobacterial infections are poorly defined. In this work, we studied the roles of CG and NE in the pulmonary resistance against Mycobacterium bovis bacillus Calmette-Guerin (BCG). CG-deficient mice and even more pronounced CG/NE-deficient mice showed significantly impaired pathogen elimination to infection with M. bovis BCG in comparison to wild-type mice. Moreover, granuloma formation was more pronounced in M. bovis BCG-infected CG/NE-deficient mice in comparison to CG-deficient and wild-type mice. A close examination of professional phagocyte subsets revealed that exclusively neutrophils shuttled CG and NE into the bronchoalveolar space of M. bovis BCG-infected mice. Accordingly, chimeric wild-type mice with a CG/NE-deficient hematopoietic system displayed significantly increased lung bacterial loads in response to M. bovis BCG infection. Therapeutically applied human CG/NE encapsulated in liposomes colocalized with mycobacteria in alveolar macrophages, as assessed by laser scanning and electron microscopy. Importantly, therapy with CG/NE-loaded liposomes significantly reduced mycobacterial loads in the lungs of mice. Together, neutrophil-derived CG and NE critically contribute to deceleration of pathogen replication during the early phase of antimycobacterial responses. In addition, to our knowledge, we show for the first time that liposomal encapsulated CG/NE exhibit therapeutic potential against pulmonary mycobacterial infections. These findings may be relevant for novel adjuvant approaches in the treatment of tuberculosis in humans. The Journal of Immunology, 2012, 188: 4476-4487.