Anas Adam A, van Lieshout Miriam H P, Claushuis Theodora A M, de Vos Alex F, Florquin Sandrine, de Boer Onno J, Hou Baidong, Van't Veer Cornelis, van der Poll Tom
Center of Infection and Immunity, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Center of Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
Am J Physiol Lung Cell Mol Physiol. 2016 Aug 1;311(2):L219-28. doi: 10.1152/ajplung.00078.2016. Epub 2016 Jun 10.
Pseudomonas aeruginosa is a flagellated pathogen frequently causing pneumonia in hospitalized patients and sufferers of chronic lung disease. Here we investigated the role of the common Toll-like receptor (TLR) adaptor myeloid differentiation factor (MyD)88 in myeloid vs. lung epithelial cells in clearance of P. aeruginosa from the airways. Mice deficient for MyD88 in lung epithelial cells (Sftpccre-MyD88-lox mice) or myeloid cells (LysMcre-MyD88-lox mice) and bone marrow chimeric mice deficient for TLR5 (the receptor recognizing Pseudomonas flagellin) in either parenchymal or hematopoietic cells were infected with P. aeruginosa via the airways. Sftpccre-MyD88-lox mice demonstrated a reduced influx of neutrophils into the bronchoalveolar space and an impaired early antibacterial defense after infection with P. aeruginosa, whereas the response of LysMcre-MyD88-lox mice did not differ from control mice. The immune-enhancing role of epithelial MyD88 was dependent on recognition of pathogen-derived flagellin by epithelial TLR5, as demonstrated by an unaltered clearance of mutant P. aeruginosa lacking flagellin from the lungs of Sftpccre-MyD88-lox mice and an impaired bacterial clearance in bone marrow chimeric mice lacking TLR5 in parenchymal cells. These data indicate that early clearance of P. aeruginosa from the airways is dependent on flagellin-TLR5-MyD88-dependent signaling in respiratory epithelial cells.
铜绿假单胞菌是一种有鞭毛的病原体，经常导致住院患者和慢性肺病患者患肺炎。在此，我们研究了常见的Toll样受体（TLR）衔接蛋白髓样分化因子（MyD）88在髓样细胞与肺上皮细胞从气道清除铜绿假单胞菌过程中的作用。通过气道用铜绿假单胞菌感染肺上皮细胞中缺乏MyD88的小鼠（Sftpccre-MyD88-lox小鼠）或髓样细胞中缺乏MyD88的小鼠（LysMcre-MyD88-lox小鼠），以及实质细胞或造血细胞中缺乏TLR5（识别铜绿假单胞菌鞭毛蛋白的受体）的骨髓嵌合小鼠。Sftpccre-MyD88-lox小鼠在感染铜绿假单胞菌后，支气管肺泡腔中中性粒细胞的流入减少，早期抗菌防御受损，而LysMcre-MyD88-lox小鼠的反应与对照小鼠没有差异。上皮细胞MyD88的免疫增强作用依赖于上皮细胞TLR5对病原体来源鞭毛蛋白的识别，这表现为缺乏鞭毛蛋白的突变型铜绿假单胞菌从Sftpccre-MyD88-lox小鼠肺部的清除未改变，以及实质细胞中缺乏TLR5的骨髓嵌合小鼠的细菌清除受损。这些数据表明，从气道早期清除铜绿假单胞菌依赖于呼吸道上皮细胞中鞭毛蛋白-TLR5-MyD88依赖性信号传导。
