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Modulation of host cell apoptosis during sepsis by alarmins

警报素对脓毒症期间宿主细胞凋亡的调节

基本信息

批准号：
20590456
负责人：
NAGAOKA Isao
金额：
$ 3万
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：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

Antimicrobial peptides (alpha- and beta-defensins, and cathelicidins) possess the potent antimicrobial activities against invading microorganisms and contribute to the innate host defense. They not only exhibit potent bactericidal activities against Gram-negative and Gram-positive bacteria but also function as immunomodulatory molecules by inducing cytokine and chemokine production, and inflammatory and immune cell activation. Neutrophil is a critical effector cell in host defense against microbial infection, and its lifespan is regulated by various pathogen- and host-derived substances. We previously revealed that human cathelicidin LL-37 and human beta-defensin (hBD)-3 suppress neutrophil apoptosis via the actions on P2X_7 nucleotide receptor and CC chemokine receptor (CCR) 6, respectively. Here, to further evaluate the role of human alpha-defensins in innate immunity, we investigated the action of human neutrophil peptides (HNPs)-1～-3 on neutrophil apoptosis.Neutrophil apoptosis was assessed using human blood neutrophils based on the morphological changes. Of note, HNP-1 most potently suppressed neutrophil apoptosis among HNP-1～-3, accompanied with the downregulation of truncated Bid (a proapoptotic protein), upregulation of Bcl-xL (an antiapoptotic protein), and inhibition of mitochondrial membrane potential change and caspase 3 activity. Interestingly, a selective P2Y_6 antagonist MRS2578 abolished the suppression of neutrophil apoptosis induced by HNP-1 as well as UDP (a P2Y_6 ligand).Collectively, these observations suggest that HNPs, especially HNP-1, can not only kill bacteria but also modulate (suppress) neutrophil apoptosis possibly via the P2Y_6 signaling. Considering their antiapoptotic action, antimicrobial peptides (LL-37, hBD-3 and HNP-1) are expected to exert an advantageous effect on host defense against bacterial infections by prolonging the lifespan of neutrophil, a major phagocyte engaged in the killing of invaded bacteria.

抗菌肽（α -防御素和β -防御素以及抗菌肽）对入侵微生物具有有效的抗菌活性，并有助于先天宿主防御。它们不仅对革兰氏阴性和革兰氏阳性细菌具有强大的杀菌活性，而且还通过诱导细胞因子和趋化因子的产生以及炎症和免疫细胞的激活而发挥免疫调节分子的作用。中性粒细胞是宿主防御微生物感染的重要效应细胞，其寿命受多种病原体和宿主源物质的调节。我们之前发现，人cathelicidin LL-37和人β -防御素(hBD)-3分别通过作用于P2X_7核苷酸受体和CC趋化因子受体（CCR） 6来抑制中性粒细胞凋亡。为了进一步探讨人α -防御素在先天免疫中的作用，我们研究了人中性粒细胞肽(HNPs)-1~-3对中性粒细胞凋亡的作用。利用人血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，在HNP-1~-3中，HNP-1最有效地抑制中性粒细胞凋亡，并伴有截断的Bid（促凋亡蛋白）的下调，Bcl-xL（抗凋亡蛋白）的上调，以及线粒体膜电位变化和caspase 3活性的抑制。有趣的是，选择性P2Y_6拮抗剂MRS2578消除了HNP-1和UDP （P2Y_6配体）诱导的中性粒细胞凋亡的抑制。总之，这些观察结果表明，HNPs，特别是HNP-1，不仅可以杀死细菌，而且可能通过P2Y_6信号通路调节（抑制）中性粒细胞凋亡。考虑到它们的抗凋亡作用，抗菌肽（LL-37、hBD-3和HNP-1）有望通过延长中性粒细胞（一种主要的吞噬细胞，负责杀死入侵的细菌）的寿命，对宿主防御细菌感染发挥有利作用。