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首页> 外文期刊>The journal of immunology >ATP Modulates Acute Inflammation In Vivo through Dual Oxidase 1–Derived H2O2 Production and NF-κB Activation
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ATP Modulates Acute Inflammation In Vivo through Dual Oxidase 1–Derived H2O2 Production and NF-κB Activation

机译：ATP通过双氧化酶1衍生的H2O2产生和NF-κB激活来调节急性炎症

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摘要

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-κB 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-κB signaling pathway.
机译：双重氧化酶1（Duox1）是NADPH氧化酶，负责伤害后在组织中形成的H2O2梯度，以触发白细胞的早期募集。关于调节从DUOX1释放H2O2的信号以及H2O2梯度是否可以在体内协调炎症反应知之甚少。在这项研究中，我们报告了斑马鱼Duox1的显性负型形式，它能够抑制组织损伤后内源性Duox1活性，H2O2释放和白细胞募集，且没有与吗啉代介导的Duox1敲除相关的副作用。使用此特定工具，我们发现组织损伤后ATP释放激活嘌呤能P2Y受体，并通过磷脂酶C（PLC）和体内细胞内钙信号传导调节Duox1活性。此外，Duox1衍生的H2O2能够触发NF-κB炎症信号通路。这些数据表明，作为早期危险信号的细胞外ATP负责通过P2YR / PLC / Ca2 +信号传导途径激活Duox1和产生H2O2，从而不仅可以在体内进行早期募集，而且还可以在体内进行调节通过激活NF-κB信号通路对伤口的白细胞的清除以及炎症反应。

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