Myeloid Differentiation Protein-2-Dependent and -Independent Neutrophil Accumulation during Escherichia coli Pneumonia
Myeloid Differentiation Protein-2-Dependent and -Independent Neutrophil Accumulation during Escherichia coli Pneumonia
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DOI：
10.1165/rcmb.2008-0152oc
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发表时间：
2009-06-01
影响因子：
6.4
通讯作者：
Jeyaseelan, Samithamby
中科院分区：
文献类型：
--
作者：
Cai, Shanshan;Zemans, Rachel L.;Jeyaseelan, Samithamby
细菌性肺炎仍然是一种严重的疾病。模式识别受体在肺炎期间中性粒细胞积聚中发挥不可或缺的作用。虽然髓样分化蛋白（MD）-2已被认为是LPS信号传导的关键分子，但MD-2在细菌感染期间肺中中性粒细胞积聚中的作用尚未被探索。在此，我们研究了MD-2在大肠杆菌LPS诱导的肺部炎症和大肠杆菌LPS诱导的肺部炎症中的作用。大肠杆菌引起的肺炎LPS诱导的CD14非依赖性中性粒细胞聚集在CD14/MD-2（-/-）小鼠中消失。用LIPS激发的MD-2（-/-）小鼠显示出减弱的中性粒细胞内流、NF-κ B活化、细胞因子/趋化因子表达和肺组织病理学。移植MD-2（+/+）骨髓的MD-2（-/-）小鼠在受到LIPS攻击时表现出肺中中性粒细胞流入和细胞因子/趋化因子表达的减少。MD-2（-/-）小鼠感染E.大肠杆菌显示肺中中性粒细胞流入和细胞因子/趋化因子表达减少，而热灭活的E. coli感染的MD-2（-/-）小鼠，中性粒细胞聚集和细胞因子/趋化因子表达均未被诱导。杆菌此外，MD-2（-/-）小鼠显示肺中细菌负荷增加和细菌传播增强。Toll样受体（TLR）-5（-/-）小鼠感染E.而MD-2/TLR5（-/-）小鼠接种E.大肠杆菌显示进一步减弱的中性粒细胞流入和受损的细菌清除。综上所述，这些新发现表明：（1）MD-2在CD14非依赖性LPS介导的中性粒细胞内流级联中的重要作用;（2）骨髓和非骨髓细胞来源的MD-2在LPS诱导的炎症中的相对重要性;（3）MD-2依赖性和MD-2非依赖性（TLR 5）信号传导在E.大肠杆菌诱导的中性粒细胞积聚和肺宿主防御。
Bacterial pneumonia remains a serious disease. Pattern recognition receptors play an integral role in neutrophil accumulation during pneumonia. Although myeloid differentiation protein (MD)-2 has been recognized as a key molecule for LPS signaling, the role of MD-2 in neutrophil accumulation in the lung during bacterial infection has not been explored. Here, we investigate the role of MD-2 in Escherichia coli LPS-induced lung inflammation and E. coli-induced pneumonia. LPS-induced CD14-independent neutrophil accumulation was abolished in CD14/MD-2(-/-) mice. MD-2(-/-) mice challenged with LIPS displayed attenuated neutrophil influx, NF-kappa B activation, cytokine/chemokine expression, and lung histopathology. MD-2(-/-) mice transplanted with MD-2(+/+) bone marrow demonstrated decreased neutrophil influx and cytokine/chemokine expression in the lungs when challenged by LIPS. MD-2(-/-) mice infected with E. coli demonstrated reduced neutrophil influx and cytokine/chemokine expression in the lungs, whereas heat-killed E. coli did not induce either neutrophil accumulation or cytokine/chemokine expression in MD-2(-/-) mice infected with E. coli. Furthermore, MD-2(-/-) mice displayed increased bacterial burden in the lungs and enhanced bacterial dissemination. Toll-like receptor (TLR)-5(-/-) mice infected with E. coli exhibited attenuated neutrophil accumulation, whereas MD-2/TLR5(-/-) mice inoculated with E. coli showed further attenuated neutrophil influx and impaired bacterial clearance. Taken together, these new findings demonstrate: (1) the important role of MD-2 in the CD14-independent LPS-mediated cascade of neutrophil influx; (2) the relative importance of bone marrow- and non-bone marrow cell-derived MD-2 in LPS-induced inflammation; and (3) the essential role of MD-2-dependent and MD-2-independent (TLR5) signaling in E. coli-induced neutrophil accumulation and pulmonary host defense.