Medical Research Council/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, W2.05, 47 Little France Crescent, Edinburgh, Scotland, UK.
Am J Respir Cell Mol Biol. 2010 Dec;43(6):692-702. doi: 10.1165/rcmb.2009-0250OC. Epub 2010 Jan 22.
Cationic host defense peptides are key, evolutionarily conserved components of the innate immune system. The human cathelicidin LL-37 is an important cationic host defense peptide up-regulated in infection and inflammation, specifically in the human lung, and was shown to enhance the pulmonary clearance of the opportunistic pathogen Pseudomonas aeruginosa in vivo by as yet undefined mechanisms. In addition to its direct microbicidal potential, LL-37 can modulate inflammation and immune mechanisms in host defense against infection, including the capacity to modulate cell death pathways. We demonstrate that at physiologically relevant concentrations of LL-37, this peptide preferentially promoted the apoptosis of infected airway epithelium, via enhanced LL-37-induced mitochondrial membrane depolarization and release of cytochrome c, with activation of caspase-9 and caspase-3 and induction of apoptosis, which only occurred in the presence of both peptide and bacteria, but not with either stimulus alone. This synergistic induction of apoptosis in infected cells was caspase-dependent, contrasting with the caspase-independent cell death induced by supraphysiologic levels of peptide alone. We demonstrate that the synergistic induction of apoptosis by LL-37 and Pseudomonas aeruginosa required specific bacteria-epithelial cell interactions with whole, live bacteria, and bacterial invasion of the epithelial cell. We propose that the LL-37-mediated apoptosis of infected, compromised airway epithelial cells may represent a novel inflammomodulatory role for this peptide in innate host defense, promoting the clearance of respiratory pathogens.
阳离子防御肽是先天免疫系统的关键、进化上保守的组成部分。人类防御肽 LL-37 是一种重要的阳离子防御肽，在感染和炎症中上调，特别是在人类肺部，并被证明通过尚未定义的机制增强了机会性病原体铜绿假单胞菌在体内的肺部清除。除了其直接的杀菌潜力外，LL-37 还可以调节宿主对感染的炎症和免疫机制的防御能力，包括调节细胞死亡途径的能力。我们证明，在生理相关浓度的 LL-37 下，该肽通过增强 LL-37 诱导的线粒体膜去极化和细胞色素 c 的释放，优先促进感染的气道上皮细胞凋亡，而 caspase-9 和 caspase-3 的激活和凋亡诱导仅发生在存在肽和细菌的情况下，而不是在没有任何一种刺激的情况下。这种感染细胞的协同诱导凋亡是半胱天冬酶依赖性的，与单独使用超生理水平的肽诱导的半胱天冬酶非依赖性细胞死亡形成对比。我们证明，LL-37 和铜绿假单胞菌协同诱导凋亡需要特定的细菌-上皮细胞相互作用，需要完整的活细菌，以及细菌对上皮细胞的侵袭。我们提出，LL-37 介导的感染、受损气道上皮细胞凋亡可能代表该肽在先天宿主防御中的一种新的炎症调节作用，促进呼吸道病原体的清除。
