Spontaneous and aging-dependent development of arthritis in NADPH oxidase 2 deficiency through altered differentiation of CD11b+and Th/Treg cells
Spontaneous and aging-dependent development of arthritis in NADPH oxidase 2 deficiency through altered differentiation of CD11b+and Th/Treg cells
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DOI：
10.1073/pnas.1012645108
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发表时间：
2011-06-07
影响因子：
11.1
通讯作者：
Hwang, Eun Sook
中科院分区：
文献类型：
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作者：
Lee, Kihyun;Won, Hee Yeon;Hwang, Eun Sook
新的证据表明 NADPH 氧化酶 (NOX) 及其活性氧 (ROS) 产物可调节多种细胞事件，包括增殖、分化和凋亡。在这项研究中，我们使用 NOX2 敲除 (KO) 小鼠研究了 NOX2 和 ROS 在免疫调节中的功能。有趣的是，NOX2 KO 小鼠自发出现关节炎，在 6-7 周龄时发病，在 15-18 周龄时发病率较高（60%）。 NOX2 KO 小鼠的关节炎严重程度随着年龄的增长而成比例增加，并且雌性小鼠的关节炎严重程度高于雄性小鼠。通过微型计算机断层扫描和关节组织学分析证实了骨破坏。 NOX2 KO 小鼠中炎症因子（包括 TNF-α、IL-1β 和 RANKL）以及血清抗 II 型胶原 IgG 水平显着升高。此外，NOX2 缺乏会扰乱衰老过程中的免疫系统。 NOX2 KO 小鼠表现出 CD11b+Gr-1+ 骨髓细胞的优先发育，通过体内 STAT3 和 ROR gamma t 的激活，大量产生促炎细胞因子并增强 IL-17 的表达。 NOX2 缺乏在体外增加了效应 Th 细胞的分化，并在体外和体内减少了 CD25+FoxP3+ Treg 细胞。此外，与WT细胞相比，将NOX2缺陷型CD4+T细胞过继转移至RAG KO小鼠体内会增加关节炎炎症。这些结果表明，NOX2缺乏影响CD11b+骨髓细胞和Th17/Treg细胞的发育，从而促进炎症细胞因子的产生和炎症性关节炎的发展，有力地支持了ROS生成在调节Th17/Treg细胞发育及其衰老过程中相关炎症免疫反应中的关键作用。
Emerging evidence indicates that NADPH oxidase (NOX) and its reactive oxygen species (ROS) products modulate a variety of cellular events, including proliferation, differentiation, and apoptosis. In this study, we investigated the functions of NOX2 and ROS in immune modulation using NOX2 knockout (KO) mice. Interestingly, NOX2 KO mice spontaneously developed arthritis with onset at 6-7 wk of age and high incidence (60%) at 15-18 wk of age. Arthritis severity in NOX2 KO mice was proportionally increased with age and higher in females than in males. Bone destruction was confirmed by microcomputed tomography scanning and histological analyses of joints. Inflammatory factors, including TNF-alpha, IL-1 beta, and RANKL, and serum level of anti-type II collagen IgG were significantly increased in NOX2 KO mice. In addition, NOX2 deficiency perturbed the immune system upon aging. NOX2 KO mice demonstrated preferred development of CD11b+Gr-1+ myeloid cells with profound production of proinflammatory cytokines and augmented expression of IL-17 through the activation of STAT3 and ROR gamma t in vivo. NOX2 deficiency increased differentiation of effector Th cells in vitro and decreased CD25+FoxP3+ Treg cells both in vitro and in vivo. Furthermore, adoptive transfer of NOX2-deficient CD4(+) T cells into RAG KO mice increased arthritic inflammation compared with WT cells. These results demonstrated that NOX2 deficiency affected the development of CD11b+ myeloid cells and Th17/Treg cells, and thus promoted inflammatory cytokine production and inflammatory arthritis development, strongly supporting a crucial role for ROS generation in the modulation of Th17/Treg cell development and its related inflammatory immune response upon aging.