ATP-binding Cassette Transporter G1 Deficiency Dysregulates Host Defense in the Lung
ATP-binding Cassette Transporter G1 Deficiency Dysregulates Host Defense in the Lung
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DOI：
10.1164/rccm.200910-1580oc
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发表时间：
2010-08-01
影响因子：
24.7
通讯作者：
Fessler, Michael B.
中科院分区：
文献类型：
--
作者：
Draper, David W.;Madenspacher, Jennifer H.;Fessler, Michael B.
理论基础：胆固醇外流转运体--三磷酸腺苷结合盒(ABC)G1基因缺失的小鼠患有肺脂病和慢性肺部炎症。目的：探讨Abcg1是否调节肺固有免疫和宿主防御，并探讨其分子/细胞机制。方法：Abcg1(+/-)和Abcg1(-/-)小鼠分别用肺内脂多糖或肺炎克雷伯菌、静脉注射肺炎克雷伯菌和腹腔注射脂多糖进行攻击。检测和主要结果：未暴露的Abcg1(-/-)小鼠的循环中性粒细胞数量正常，但中性粒细胞向肺泡和肺实质募集的增加，以及稳态时肺泡内细胞因子和趋化因子的增加。肺内注射脂多糖或肺炎克雷伯菌后，Abcg1(-/-)小鼠表现出中性粒细胞在肺泡内进一步聚集和脱颗粒，肺泡内细胞因子/趋化因子诱导升高。肺泡巨噬细胞Abcg1是关键，因为造血细胞中Abcg1缺乏足以增强体内的反应，而Abcg1(-/-)肺泡巨噬细胞采用“泡沫细胞”表型，并在体外具有高反应性。Abcg1-/-小鼠对肺炎克雷伯菌的肺区划和清除增加，表明宿主防御增强。相反，Abcg1(+/+)和Abcg1(-/-)小鼠对肺炎克雷伯菌静脉注射和腹腔注射内毒素的反应相同，提示Abcg1以组织选择性的方式调节先天免疫。结论：Abcg1(/-)小鼠具有以造血细胞为主的增强的肺宿主防御反应。
Rationale: Mice with genetic deletion of the cholesterol efflux transporter, ATP-binding cassette (ABC) G1, have pulmonary lipidosis and chronic pulmonary inflammation. Whether ABCG1 regulates host defense is unknown.Objectives: To determine whether ABCG1 regulates pulmonary innate immunity and host defense, and to investigate the underlying molecular/cellular mechanisms.Methods: Abcg1(+/-) and Abcg1(-/-) mice were challenged with intrapulmonary lipopolysaccharide (LPS) or Klebsiella pneumoniae, intravenous K pneumoniae, or intra peritoneal LPS. Phenotypic responses were profiled Bone marrow chimeras and in vitro assays were used to differentiate and characterize the role of hematopoietic versus nonhematopoietic ABCG1 in host defense.Measurements and Main Results: Unexposed Abcg1(-/-) mice had normal numbers of circulating neutrophils, but increased neutrophil recruitment to the airspace and lung parenchyma, and increased airspace cytokines and chemokines in the steady state. After intrapulmonary LPS or K. pneumoniae, Abcg1(-/-) mice displayed exaggerated further neutrophil recruitment to and degranulation in the airspace, and elevated airspace cytokine/chemokine induction. Alveolar macrophage ABCG1 was critical, as ABCG1 deficiency in hematopoietic cells was sufficient to enhance responses in vivo, and Abcg1(-/-) alveolar macrophages adopted a "foam cell" phenotype, and were hyperresponsive ex vivo. Pulmonary compartmentalization and clearance of K pneumoniae were increased in Abcg1-/- mice, indicating enhanced host defense. By contrast, Abcg1(+/+) and Abcg1(-/-) mice had equivalent responses to intravenous K pneumoniae and intraperitoneal LPS, suggesting that ABCG1 regulates innate immunity in a tissue-selective manner.Conclusions: Abcgl1 (/-) mice have an enhanced pulmonary host defense response driven predominantly by hematopoietic cells.