ATP Modulates Acute Inflammation In Vivo through Dual Oxidase 1-Derived H2O2 Production and NF-κB Activation
ATP Modulates Acute Inflammation In Vivo through Dual Oxidase 1-Derived H2O2 Production and NF-κB Activation
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DOI：
10.4049/jimmunol.1302902
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发表时间：
2014-06-15
影响因子：
4.4
通讯作者：
Mulero, Victoriano
中科院分区：
文献类型：
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作者：
de Oliveira, Sofia;Lopez-Munoz, Azucena;Mulero, Victoriano
双重氧化酶1(Duox1)是一种NADPH氧化酶，负责损伤后组织中形成的过氧化氢梯度，从而触发白细胞的早期募集。关于调节DUOX1释放过氧化氢的信号以及过氧化氢梯度是否能在体内协调炎症反应，人们知之甚少。在这项研究中，我们报道了一种显性-负性形式的斑马鱼Duox1，它能够抑制组织损伤后内源性Duox1的活性、H_2O_2的释放和白细胞的募集，并且没有与吗啉介导的Duox1基因敲除相关的副作用。利用这一工具，我们发现组织损伤后的ATP释放激活了嘌呤能的P2Y受体，并通过磷脂酶C(PLC)和细胞内钙信号调节Duox1的活性。此外，Duox1衍生的双氧水能够触发核因子-kappaB炎症信号通路。这些数据表明，细胞外ATP作为早期危险信号，通过P2YR/PLC/Ca~(2+)信号通路激活Duox1并产生H_2O_2，从而不仅能够调节体内白细胞对伤口的早期募集，而且通过激活NF-kappa B信号通路来调节炎症反应。
Dual oxidase 1 (Duox1) is the NADPH oxidase responsible for the H2O2 gradient formed in tissues after injury to trigger the early recruitment of leukocytes. Little is known about the signals that modulate H2O2 release from DUOX1 and whether the H2O2 gradient can orchestrate the inflammatory response in vivo. In this study, we report on a dominant-negative form of zebrafish Duox1 that is able to inhibit endogenous Duox1 activity, H2O2 release and leukocyte recruitment after tissue injury, with none of the side effects associated with morpholino-mediated Duox1 knockdown. Using this specific tool, we found that ATP release following tissue injury activates purinergic P2Y receptors, and modulates Duox1 activity through phospholipase C (PLC) and intracellular calcium signaling in vivo. Furthermore, Duox1-derived H2O2 is able to trigger the NF-kappa B inflammatory signaling pathway. These data reveal that extracellular ATP acting as an early danger signal is responsible for the activation of Duox1 via a P2YR/PLC/Ca2+ signaling pathway and the production of H2O2, which, in turn, is able to modulate in vivo not only the early recruitment of leukocytes to the wound but also the inflammatory response through activation of the NF-kappa B signaling pathway.