Reiniger Nina, Lee Martin M, Coleman Fadie T, Ray Christopher, Golan David E, Pier Gerald B
Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
Infect Immun. 2007 Apr;75(4):1598-608. doi: 10.1128/IAI.01980-06. Epub 2007 Feb 5.
Innate immunity is critical for clearing Pseudomonas aeruginosa from the lungs. In response to P. aeruginosa infection, a central transcriptional regulator of innate immunity-NF-kappaB-is translocated within 15 min to the nuclei of respiratory epithelial cells expressing wild-type (WT) cystic fibrosis (CF) transmembrane conductance regulator (CFTR). P. aeruginosa clearance from lungs is impaired in CF, and rapid NF-kappaB nuclear translocation is defective in cells with mutant or missing CFTR. We used WT and mutant P. aeruginosa and strains of transgenic mice lacking molecules involved in innate immunity to identify additional mediators required for P. aeruginosa-induced rapid NF-kappaB nuclear translocation in lung epithelia. We found neither Toll-like receptor 2 (TLR2) nor TLR4 nor TLR5 were required for this response. However, both MyD88-deficient mice and interleukin-1 receptor (IL-1R)-deficient mice failed to rapidly translocate NF-kappaB to the nuclei of respiratory epithelial cells in response to P. aeruginosa. Cultured human bronchial epithelial cells rapidly released IL-1beta in response to P. aeruginosa; this process was maximized by expression of WT-CFTR and dramatically muted in cells with DeltaF508-CFTR. The IL-1R antagonist blocked P. aeruginosa-induced NF-kappaB nuclear translocation. Oral inoculation via drinking water of IL-1R knockout mice resulted in higher rates of lung colonization and elevated P. aeruginosa-specific antibody titers in a manner analogous to that of CFTR-deficient mice. Overall, rapid IL-1 release and signaling through IL-1R represent key steps in the innate immune response to P. aeruginosa infection, and this process is deficient in cells lacking functional CFTR.
固有免疫对于清除肺部的铜绿假单胞菌至关重要。针对铜绿假单胞菌感染，固有免疫的一个核心转录调节因子——核因子κB（NF-κB）在15分钟内转移至表达野生型（WT）囊性纤维化（CF）跨膜电导调节因子（CFTR）的呼吸道上皮细胞核内。在囊性纤维化患者中，肺部清除铜绿假单胞菌的能力受损，并且在CFTR突变或缺失的细胞中，NF-κB的快速核转位存在缺陷。我们使用野生型和突变型铜绿假单胞菌以及缺乏固有免疫相关分子的转基因小鼠品系，以确定肺上皮细胞中铜绿假单胞菌诱导的NF-κB快速核转位所需的其他介质。我们发现，这种反应既不需要Toll样受体2（TLR2），也不需要TLR4或TLR5。然而，MyD88缺陷小鼠和白细胞介素-1受体（IL-1R）缺陷小鼠在响应铜绿假单胞菌时均未能将NF-κB快速转移至呼吸道上皮细胞核内。培养的人支气管上皮细胞在响应铜绿假单胞菌时会快速释放IL-1β；这一过程通过WT-CFTR的表达得以最大化，而在具有ΔF508-CFTR的细胞中则显著减弱。IL-1R拮抗剂可阻断铜绿假单胞菌诱导的NF-κB核转位。通过饮用水对IL-1R基因敲除小鼠进行口服接种，导致肺部定植率更高，并且铜绿假单胞菌特异性抗体滴度升高，其方式类似于CFTR缺陷小鼠。总体而言，快速的IL-1释放以及通过IL-1R的信号传导代表了对铜绿假单胞菌感染的固有免疫反应中的关键步骤，并且这一过程在缺乏功能性CFTR的细胞中存在缺陷。
