The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium.
The human cathelicidin LL-37 preferentially promotes apoptosis of infected airway epithelium.
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DOI：
10.1165/rcmb.2009-0250oc
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发表时间：
2010-12
影响因子：
6.4
通讯作者：
Davidson DJ
中科院分区：
文献类型：
--
作者：
Barlow PG;Beaumont PE;Cosseau C;Mackellar A;Wilkinson TS;Hancock RE;Haslett C;Govan JR;Simpson AJ;Davidson DJ
阳离子宿主防御肽是先天免疫系统的关键、进化上保守的组分。人凯萨林菌素LL-37是一种重要的阳离子宿主防御肽，在感染和炎症中上调，包括在人肺中，并且已显示通过尚未确定的机制在体内增强机会致病菌铜绿假单胞菌的肺清除。除了直接杀微生物的潜力外，LL-37还可以调节宿主防御感染的炎症和免疫机制，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，这种肽优先促进受感染的气道上皮细胞的凋亡，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，激活半胱天冬酶-9和-3和诱导细胞凋亡，这只发生在肽和细菌的存在下，但不是单独的刺激。这种协同诱导感染细胞凋亡是半胱天冬酶依赖性的，与单独的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细胞凋亡需要特定的细菌-上皮细胞与整个活细菌的相互作用以及上皮细胞的细菌入侵。我们提出，LL-37介导的感染，受损的气道上皮细胞凋亡可能代表了一种新的炎症调节作用，这种肽在先天宿主防御，促进呼吸道病原体的清除。
Cationic host defence peptides are key, evolutionarily conserved components of the innate immune system. The human cathelicidin LL-37 is an important cationic host defence peptide upregulated in infection and inflammation, including in the human lung, and has been shown to enhance the pulmonary clearance of the opportunistic pathogen Pseudomonas aeruginosa in vivo by as yet undefined mechanisms. In addition to direct microbicidal potential, LL-37 can modulate inflammation and immune mechanisms in host defence 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 depolarisation and release of cytochrome c, with activation of caspases -9 and -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 supra-physiological levels of peptide alone. We demonstrate that the synergistic induction of apoptosis by LL-37 and P. aeruginosa required specific bacteria-epithelial cell interaction with whole, live bacteria, and bacterial invasion of the epithelial cell. We propose that LL-37-mediated apoptosis of infected, compromised airway epithelial cells might represent a novel inflammomodulatory role for this peptide in innate host defence, promoting clearance of respiratory pathogens.