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Molecular mechanism for the regulation of septic shock by endogenous antimicrobial cathelicidin peptides

内源性抗菌抗菌肽调节感染性休克的分子机制

基本信息

批准号：
17590401
负责人：
NAGAOKA Isao
金额：
$ 2.39万
依托单位：
Juntendo University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

Peptide antibiotics possess the potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. An antibacterial cathelicidin, human LL-37 and hBDs (human B-defensins) not only exhibits potent bactericidal activities but also functions as a chemoattractant for immune cells including neutrophils. During bacterial infections including sepsis, the lifespan of neutrophils is regulated by various pathogen and host-derived substances. Here, to further evaluate the role of LL-37 and hBDs in innate immunity, we investigated their actions on neutrophil apoptosis.Neutrophil apoptosis was assessed using human blood neutrophils based on the morphological changes. Of note, LL-37 and HBD-3 suppressed neutrophil apoptosis, accompanied with the phosphorylation of ERK-1/-2, expression of Bcl-XL (an anti-apoptotic protein) and inhibition of caspase 3 activity. Interestingly, LL-37- and hBD-3-induced suppression of neutrophil apoptosis was attenuated by the antagonists for formyl-peptide receptor-like 1 (FPRL1) and P2X7 nucleotide receptor, and a chemokine receptor CCR6, respectively.Collectively, these observations indicate that LL-37 and hBD-3 can not only kill bacteria but also modulate (suppress) neutrophil apoptosis via the activation of FPRL1 and P2X7, and CCR6, respectively, in bacterial infections. Suppression of neutrophil apoptosis results in the prolongation of their life span and may be advantageous for host defense against bacterial invasion. However, the suppressed neutrophil apoptosis may causes the uncontrolled release of cytotoxic metabolites and pro-inflammatory substances (i.e. reactive oxygen species and proteases), which leads to the amplification of systemic inflammation, tissue injury and organ failure observed in sepsis.

肽抗生素具有针对入侵微生物的有效抗菌活性，并有助于宿主的先天防御。抗菌抗菌肽、人 LL-37 和 hBD（人 B 防御素）不仅具有有效的杀菌活性，而且还可以作为包括中性粒细胞在内的免疫细胞的化学引诱剂。在包括脓毒症在内的细菌感染期间，中性粒细胞的寿命受到各种病原体和宿主衍生物质的调节。在这里，为了进一步评估 LL-37 和 hBD 在先天免疫中的作用，我们研究了它们对中性粒细胞凋亡的作用。使用人血液中性粒细胞根据形态学变化评估中性粒细胞凋亡。值得注意的是，LL-37 和 HBD-3 抑制中性粒细胞凋亡，并伴有 ERK-1/-2 的磷酸化、Bcl-XL（一种抗凋亡蛋白）的表达以及 caspase 3 活性的抑制。有趣的是，甲酰基肽受体样 1 (FPRL1) 和 P2X7 核苷酸受体以及趋化因子受体 CCR6 的拮抗剂分别减弱了 LL-37 和 hBD-3 诱导的中性粒细胞凋亡抑制。总的来说，这些观察结果表明 LL-37 和 hBD-3 不仅可以杀死细菌，还可以调节细菌在细菌感染中分别通过激活 FPRL1 和 P2X7 以及 CCR6 来（抑制）中性粒细胞凋亡。抑制中性粒细胞凋亡可延长其寿命，并可能有利于宿主防御细菌入侵。然而，中性粒细胞凋亡受到抑制可能导致细胞毒性代谢物和促炎物质（即活性氧和蛋白酶）不受控制地释放，从而导致脓毒症中观察到的全身炎症、组织损伤和器官衰竭的放大。