Department of Ophthalmology, Wayne State University, Detroit, MI 48201, USA.
J Immunol. 2010 Jul 15;185(2):1142-9. doi: 10.4049/jimmunol.1000509. Epub 2010 Jun 21.
TLRs are required for generation of protective lung mucosal immune responses against microbial pathogens. In this study, we evaluated the effect of the TLR5 ligand flagellin on stimulation of antibacterial mucosal immunity in a lethal murine Pseudomonas aeruginosa pneumonia model. The intranasal pretreatment of mice with purified P. aeruginosa flagellin induced strong protection against intratracheal P. aeruginosa-induced lethality, which was attributable to markedly improved bacterial clearance, reduced dissemination, and decreased alveolar permeability. The protective effects of flagellin on survival required TLR5 and were observed even in the absence of neutrophils. Flagellin induced strong induction of innate genes, most notably the antimicrobial peptide cathelicidin-related antimicrobial peptide. Finally, flagellin-induced protection was partially abrogated in cathelicidin-related antimicrobial peptide-deficient mice. Our findings illustrate the profound stimulatory effect of flagellin on lung mucosal innate immunity, a response that might be exploited therapeutically to prevent the development of gram-negative bacterial infection of the respiratory tract.
TLRs 是产生针对微生物病原体的保护性肺部黏膜免疫反应所必需的。在这项研究中，我们评估了 TLR5 配体鞭毛蛋白对致命性铜绿假单胞菌肺炎小鼠模型中抗菌黏膜免疫刺激的影响。用纯化的铜绿假单胞菌鞭毛蛋白对小鼠进行鼻内预处理，可诱导对气管内铜绿假单胞菌诱导的致死性的强烈保护，这归因于明显改善的细菌清除率、减少的传播和降低的肺泡通透性。鞭毛蛋白对存活的保护作用需要 TLR5，即使在没有中性粒细胞的情况下也能观察到。鞭毛蛋白强烈诱导先天基因的表达，特别是抗菌肽 cathelicidin 相关抗菌肽。最后，在 cathelicidin 相关抗菌肽缺陷小鼠中，鞭毛蛋白诱导的保护作用部分被阻断。我们的研究结果说明了鞭毛蛋白对肺部黏膜先天免疫的深远刺激作用，这种反应可能被利用于治疗，以防止呼吸道革兰氏阴性细菌感染的发展。
