Cai Shanshan, Zemans Rachel L, Young Scott K, Worthen G Scott, Jeyaseelan Samithamby
Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Louisiana State University (LSU), Baton Rouge, Louisiana 70803, USA.
Am J Respir Cell Mol Biol. 2009 Jun;40(6):701-9. doi: 10.1165/rcmb.2008-0152OC. Epub 2008 Nov 6.
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 LPS displayed attenuated neutrophil influx, NF-kappaB 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 LPS. 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.
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的积聚中起着不可或缺的作用。尽管髓样分化蛋白（MD）-2已被认为是LPS信号传导的关键分子，但MD-2在细菌感染期间肺部中性粒细胞积聚中的作用尚未得到探索。在此，我们研究MD-2在大肠杆菌LPS诱导的肺部炎症和大肠杆菌诱导的肺炎中的作用。在CD14/MD-2（-/-）小鼠中，LPS诱导的不依赖CD14的中性粒细胞积聚被消除。用LPS攻击的MD-2（-/-）小鼠表现出中性粒细胞流入减少、NF-κB激活减弱、细胞因子/趋化因子表达降低以及肺部组织病理学改变。移植了MD-2（+/+）骨髓的MD-2（-/-）小鼠在受到LPS攻击时，肺部中性粒细胞流入和细胞因子/趋化因子表达减少。感染大肠杆菌的MD-2（-/-）小鼠肺部中性粒细胞流入和细胞因子/趋化因子表达降低，而热灭活的大肠杆菌在感染大肠杆菌的MD-2（-/-）小鼠中既不诱导中性粒细胞积聚也不诱导细胞因子/趋化因子表达。此外，MD-2（-/-）小鼠肺部细菌载量增加且细菌播散增强。感染大肠杆菌的Toll样受体（TLR）-5（-/-）小鼠中性粒细胞积聚减弱，而接种大肠杆菌的MD-2/TLR5（-/-）小鼠中性粒细胞流入进一步减弱且细菌清除受损。综上所述，这些新发现表明：（1）MD-2在不依赖CD14的LPS介导的中性粒细胞流入级联反应中起重要作用；（2）骨髓源性和非骨髓源性MD-2在LPS诱导的炎症中的相对重要性；以及（3）MD-2依赖性和MD-2非依赖性（TLR5）信号传导在大肠杆菌诱导的中性粒细胞积聚和肺部宿主防御中的重要作用。
