Brucella Infection Regulates Thioredoxin-Interacting Protein Expression to Facilitate Intracellular Survival by Reducing the Production of Nitric Oxide and Reactive Oxygen Species
Brucella Infection Regulates Thioredoxin-Interacting Protein Expression to Facilitate Intracellular Survival by Reducing the Production of Nitric Oxide and Reactive Oxygen Species
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DOI：
10.4049/jimmunol.1801550
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发表时间：
2020-02-01
影响因子：
4.4
通讯作者：
Yu, Shengqing
中科院分区：
文献类型：
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作者：
Hu, Hai;Tian, Mingxing;Yu, Shengqing
硫氧还蛋白相互作用蛋白（TXNIP）是一种多功能蛋白，在肿瘤抑制、氧化应激和炎症反应中发挥作用。然而，TXNIP如何在微生物感染过程中发挥作用的报道很少。在这项研究中，我们证明，布鲁氏菌感染减少TXNIP的表达，以促进其在巨噬细胞的细胞内生长，通过减少NO和活性氧（ROS）的产生。在布鲁氏菌感染后，TXNIP敲除的RAW264.7细胞产生的NO和ROS水平显著低于野生型RAW264.7细胞。诱导型一氧化氮合酶（iNOS）抑制剂治疗降低NO水平，这导致TXNIP表达的剂量依赖性恢复，表明TXNIP的表达受NO调节。此外，iNOS的表达和NO的产生依赖于布鲁氏菌的IV型分泌系统。此外，布鲁氏菌感染降低了骨髓源性巨噬细胞和小鼠肺和脾中TXNIP的表达。骨髓源性巨噬细胞中TXNIP表达的敲低增加了布鲁氏菌的细胞内存活。这些发现揭示了以下内容：1）TXNIP是通过减少NO和ROS的产生来促进布鲁氏菌细胞内存活的新分子; 2）NO的负反馈调节系统赋予针对iNOS介导的抗菌作用的保护。阐明这一机制可能揭示了一种新的宿主监视细菌细胞内生存的途径。
Thioredoxin-interacting protein (TXNIP) is a multifunctional protein that functions in tumor suppression, oxidative stress, and inflammatory responses. However, how TXNIP functions during microbial infections is rarely reported. In this study, we demonstrate that Brucella infection decreased TXNIP expression to promote its intracellular growth in macrophages by decreasing the production of NO and reactive oxygen species (ROS). Following Brucella abortus infection, TXNIP knockout RAW264.7 cells produced significantly lower levels of NO and ROS, compared with wild-type RAW264.7 cells. Inducible NO synthase (iNOS) inhibitor treatment reduced NO levels, which resulted in a dose-dependent restoration of TXNIP expression, demonstrating that the expression of TXNIP is regulated by NO. In addition, the expression of iNOS and the production of NO were dependent on the type IV secretion system of Brucella. Moreover, Brucella infection reduced TXNIP expression in bone marrow-derived macrophages and mouse lung and spleen. Knocked down of the TXNIP expression in bone marrow-derived macrophages increased intracellular survival of Brucella. These findings revealed the following: 1) TXNIP is a novel molecule to promote Brucella intracellular survival by reducing the production of NO and ROS; 2) a negative feedback-regulation system of NO confers protection against iNOS-mediated antibacterial effects. The elucidation of this mechanism may reveal a novel host surveillance pathway for bacterial intracellular survival.