Role of NOX2-Derived Reactive Oxygen Species in NK Cell-Mediated Control of Murine Melanoma Metastasis
Role of NOX2-Derived Reactive Oxygen Species in NK Cell-Mediated Control of Murine Melanoma Metastasis
复制标题
DOI：
10.1158/2326-6066.cir-16-0382
复制
发表时间：
2017-09-01
影响因子：
10.1
通讯作者：
Martner, Anna
中科院分区：
文献类型：
--
作者：
Aydin, Ebru;Johansson, Junko;Martner, Anna
髓样细胞的NADPH氧化酶，NOX 2，产生活性氧（ROS），以消除病原体和恶性细胞。还提出了NOX 2衍生的ROS抑制自然杀伤（NK）细胞和已建立的肿瘤的微环境中的其他NK淋巴细胞的功能。NOX 2和ROS影响远处转移过程的机制仅得到部分探索。在这里，我们利用遗传NOX 2缺陷小鼠和药理学抑制NOX 2阐明的作用，NOX 2的血行转移的黑色素瘤细胞。在静脉内接种B16 F1或B16 F10细胞后，与Nox 2充足的野生型（WT）小鼠相比，B6.129 S6 Cybb（m1 DinK）（Nox 2-KO）小鼠的肺转移形成减少。全身治疗与NOX 2抑制剂组胺二盐酸盐（HDC）减少黑色素瘤转移，并增强了IFN γ产生的NK细胞浸润到WT的肺，但没有Nox 2-KO小鼠。IFN γ缺陷型B6.129S7-Ifngt（m1 Ts）/ J小鼠易于发生黑素瘤转移，并且对HDC的体内治疗无应答。我们认为，NOX 2衍生的ROS通过下调NK细胞功能促进黑色素瘤细胞的转移，并且抑制NOX 2可以恢复IFN γ依赖的NK细胞介导的黑色素瘤细胞清除。(C)2017年AACR。
The NADPH oxidase of myeloid cells, NOX2, generates reactive oxygen species (ROS) to eliminate pathogens and malignant cells. NOX2-derived ROS have also been proposed to dampen functions of natural killer (NK) cells and other antineoplastic lymphocytes in the microenvironment of established tumors. The mechanisms by which NOX2 and ROS influence the process of distant metastasis have only been partially explored. Here, we utilized genetically NOX2-deficient mice and pharmacologic inhibition of NOX2 to elucidate the role of NOX2 for the hematogenous metastasis of melanoma cells. After intravenous inoculation of B16F1 or B16F10 cells, lung metastasis formation was reduced in B6.129S6 Cybb(m1DinK) (Nox2-KO) versus Nox2-sufficient wild-type (WT) mice. Systemic treatment with the NOX2-inhibitor histamine dihydrochloride (HDC) reduced melanoma metastasis and enhanced the infiltration of IFN gamma-producing NK cells into lungs of WT but not of Nox2-KO mice. IFN gamma-deficient B6.129S7-Ifngt(m1Ts)/ J mice were prone to develop melanoma metastases and did not respond to in vivo treatment with HDC. We propose that NOX2-derived ROS facilitate metastasis of melanoma cells by downmodulating NK-cell function and that inhibition of NOX2 may restore IFN gamma-dependent, NK cell-mediated clearance of melanoma cells. (C) 2017 AACR.