2-Arachidonoyl-glycerol- and arachidonic acid-stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV-1, and RSV
2-Arachidonoyl-glycerol- and arachidonic acid-stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV-1, and RSV
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DOI：
10.1189/jlb.0412200
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发表时间：
2013-02-01
影响因子：
5.5
通讯作者：
Flamand, Nicolas
中科院分区：
文献类型：
--
作者：
Chouinard, Francois;Turcotte, Caroline;Flamand, Nicolas
内源性大麻素2-AG对其水解成AA高度敏感，AA通过LTB 4的从头生物合成激活中性粒细胞，而不依赖于CB激活。在这项研究中，我们表明，2-AG和AA刺激中性粒细胞释放抗菌效应。用纳摩尔浓度的2-AG和AA活化的中性粒细胞的上清液确实抑制HSV-1和RSV的感染性。此外，2-AG和AA刺激的中性粒细胞的上清液强烈损害大肠杆菌和金黄色葡萄球菌的生长。这与大量（微克）α-防御素以及有限量（纳克）LL-37的释放相关。AA和2-AG的上述作用可通过抑制LTB 4的生物合成或阻断BLT 1而被阻断。重要的是，CB 2受体激动剂和拮抗剂都不能分别模拟或阻止2-AG的作用。事实上，qPCR数据显示，污染性嗜酸性粒细胞表达的CB 2受体mRNA比纯化的中性粒细胞多100倍，表明人中性粒细胞的CB 2受体表达有限，并且污染性嗜酸性粒细胞可能是先前记录的新鲜分离的人中性粒细胞的CB 2表达的原因。2-AG快速转化为AA并随后代谢为LTB 4，促进2-AG和AA作为中性粒细胞的多功能激活剂，主要通过激活BLT 1发挥其作用。考虑到AA或2-AG的纳摩尔浓度足以损害病毒感染性，这表明2-AG和AA作为体内宿主防御的调节剂的潜在生理作用。J. Leukoc. 93：267-276; 2013.
The endocannabinoid 2-AG is highly susceptible to its hydrolysis into AA, which activates neutrophils through de novo LTB4 biosynthesis, independently of CB activation. In this study, we show that 2-AG and AA stimulate neutrophils to release antimicrobial effectors. Supernatants of neutrophils activated with nanomolar concentrations of 2-AG and AA indeed inhibited the infectivity of HSV-1 and RSV. Additionally, the supernatants of 2-AG-and AA-stimulated neutrophils strongly impaired the growth of Escherichia coli and Staphylococcus aureus. This correlated with the release of a large amount (micrograms) of alpha-defensins, as well as a limited amount (nanograms) of LL-37. All the effects of AA and 2-AG mentioned above were prevented by inhibiting LTB4 biosynthesis or by blocking BLT1. Importantly, neither CB2 receptor agonists nor antagonists could mimic nor prevent the effects of 2-AG, respectively. In fact, qPCR data show that contaminating eosinophils express similar to 100-fold more CB2 receptor mRNA than purified neutrophils, suggesting that CB2 receptor expression by human neutrophils is limited and that contaminating eosinophils are likely responsible for the previously documented CB2 expression by freshly isolated human neutrophils. The rapid conversion of 2-AG to AA and their subsequent metabolism into LTB4 promote 2-AG and AA as multifunctional activators of neutrophils, mainly exerting their effects by activating the BLT1. Considering that nanomolar concentrations of AA or 2-AG were sufficient to impair viral infectivity, this suggests potential physiological roles for 2-AG and AA as regulators of host defense in vivo. J. Leukoc. Biol. 93: 267-276; 2013.