Lung-Specific Overexpression of CC Chemokine Ligand (CCL) 2 Enhances the Host Defense to Streptococcus pneumoniae Infection in Mice: Role of the CCL2-CCR2 Axis1
Lung-Specific Overexpression of CC Chemokine Ligand (CCL) 2 Enhances the Host Defense to Streptococcus pneumoniae Infection in Mice: Role of the CCL2-CCR2 Axis1
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DOI：
10.4049/jimmunol.178.9.5828
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发表时间：
2007-05
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影响因子：
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通讯作者：
C. Winter;K. Taut;Mrigank Srivastava;F. Länger;M. Mack;D. Briles;J. Paton;R. Maus;T. Welte;M. Gunn;U. Maus
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作者：
C. Winter;K. Taut;Mrigank Srivastava;F. Länger;M. Mack;D. Briles;J. Paton;R. Maus;T. Welte;M. Gunn;U. Maus
单核吞噬细胞是宿主肺部对吸入细菌病原体的先天防御的关键组成部分。单核细胞趋化蛋白 CCL2 在炎症性单核吞噬细胞募集中发挥着关键作用。在这项研究中，我们测试了这样的假设：增加 CCL2 依赖性单核吞噬细胞的募集将改善肺部对肺炎链球菌感染的先天宿主防御。在 II 型肺泡上皮细胞中过度表达人 CCL2 蛋白并将其分泌到肺泡气腔中的 CCL2 转基因小鼠在受到肺炎链球菌攻击时表现出与野生型小鼠类似的促炎介质反应和中性粒细胞性肺泡炎。然而，与野生型小鼠相比，CCL2 过表达小鼠的肺炎球菌清除率和存活率有所提高，这与肺炎球菌攻击后肺单核吞噬细胞亚群积累的大幅增加有关。令人惊讶的是，CCL2 过表达小鼠在肺炎球菌攻击后出现闭塞性细支气管炎。应用抗 CCR2 Ab MC21 阻断 CCL2 过表达小鼠的 CCL2-CCR2 轴，虽然完全消除了闭塞性细支气管炎，但导致进行性肺炎球菌肺炎。总的来说，这些发现证明了 CCL2-CCR2 轴在细菌攻击后调节解决/修复和重塑过程中的重要性，并表明压倒性的先天免疫反应可能会引发细菌性肺部感染中闭塞性细支气管炎的形成。
Mononuclear phagocytes are critical components of the innate host defense of the lung to inhaled bacterial pathogens. The monocyte chemotactic protein CCL2 plays a pivotal role in inflammatory mononuclear phagocyte recruitment. In this study, we tested the hypothesis that increased CCL2-dependent mononuclear phagocyte recruitment would improve lung innate host defense to infection with Streptococcus pneumoniae. CCL2 transgenic mice that overexpress human CCL2 protein in type II alveolar epithelial cells and secrete it into the alveolar air space showed a similar proinflammatory mediator response and neutrophilic alveolitis to challenge with S. pneumoniae as wild-type mice. However, CCL2 overexpressing mice showed an improved pneumococcal clearance and survival compared with wild-type mice that was associated with substantially increased lung mononuclear phagocyte subset accumulations upon pneumococcal challenge. Surprisingly, CCL2 overexpressing mice developed bronchiolitis obliterans upon pneumococcal challenge. Application of anti-CCR2 Ab MC21 to block the CCL2-CCR2 axis in CCL2 overexpressing mice, though completely abrogating bronchiolitis obliterans, led to progressive pneumococcal pneumonia. Collectively, these findings demonstrate the importance of the CCL2-CCR2 axis in the regulation of both the resolution/repair and remodelling processes after bacterial challenge and suggest that overwhelming innate immune responses may trigger bronchiolitis obliterans formation in bacterial lung infections.