Resveratrol Inhibits the TRIF-Dependent Pathway by Upregulating Sterile Alpha and Armadillo Motif Protein, Contributing to Anti-Inflammatory Effects after Respiratory Syncytial Virus Infection
Resveratrol Inhibits the TRIF-Dependent Pathway by Upregulating Sterile Alpha and Armadillo Motif Protein, Contributing to Anti-Inflammatory Effects after Respiratory Syncytial Virus Infection
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白藜芦醇通过上调无菌 Alpha 和犰狳基序蛋白抑制 TRIF 依赖性途径，有助于呼吸道合胞病毒感染后的抗炎作用
DOI：
10.1128/jvi.03637-13
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发表时间：
2014-04-01
影响因子：
5.4
通讯作者：
Liu, Enmei
中科院分区：
文献类型：
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作者：
Liu, Tiantian;Zang, Na;Liu, Enmei
摘要 呼吸道合胞病毒（RSV）是幼儿下呼吸道感染的最重要原因，也是全球婴儿住院的主要原因。对 RSV 的不受控制的反应是由 Toll 样受体 (TLR) 介导的免疫反应介导的。白藜芦醇具有抗 RSV 活性，并且是 TRIF/TBK1/IRF-3 复合物的抑制剂。我们假设白藜芦醇通过上调 RSV 感染后的 SARM 来抑制 TRIF 依赖性途径。 BALB/c小鼠感染RSV并在接种后1小时注射白藜芦醇。将 SARM 短干扰 RNA 给予 RSV 感染和白藜芦醇治疗的小鼠。通过全身体积描记法测量肺功能，检查肺组织病理学，并对支气管肺泡灌洗液中的淋巴细胞进行定量。通过蛋白质印迹分析检测肺中 SARM 和 TRIF 蛋白的表达。通过酶联免疫吸附测定（ELISA）评估支气管肺泡灌洗液（BALF）中γ干扰素的表达。 RSV感染后SARM表达减少，TRIF表达增加。 RSV感染后，白藜芦醇增加SARM表达并降低TRIF表达。白藜芦醇治疗小鼠中的 SARM 敲除增强了 γ 干扰素的产生、RSV 诱导的气道炎症和气道高反应性 (AHR)。白藜芦醇降低 TRIF 表达并阻止 RSV 介导的 SARM 表达减少。白藜芦醇介导的 TRIF 依赖性途径的抑制可能依赖于 SARM 表达。重要性 我们的研究提供了对 RSV 感染反应的先天免疫调节的见解。结果表明，白藜芦醇介导的 SARM 改变具有针对 TLR 介导的免疫反应失调引起的 RSV 免疫病理学的治疗潜力。最终，深入了解 TLR 接头蛋白与严重 RSV 感染发生之间的复杂相互作用可能会导致新的治疗策略，例如 TLR 佐剂。
ABSTRACT Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in young children and the leading cause of infant hospitalization worldwide. Uncontrolled response to RSV is mediated by a toll-like receptor (TLR)-mediated immune response. Resveratrol possesses anti-RSV activity and is an inhibitor of the TRIF/TBK1/IRF-3 complex. We hypothesize that resveratrol inhibits the TRIF-dependent pathway through upregulation of SARM post-RSV infection. BALB/c mice were infected with RSV and were injected with resveratrol 1 h postinoculation. SARM short interfering RNA was administered to RSV-infected and resveratrol-treated mice. Lung function was measured by whole-body plethysmography, lung histopathology was examined, and lymphocytes in bronchoalveolar lavage fluid were quantified. SARM and TRIF protein expression were detected in the lung by Western blot analyses. The expression of gamma interferon in bronchoalveolar lavage fluid (BALF) was evaluated by enzyme-linked immunosorbent assay (ELISA). SARM expression was reduced and TRIF expression was increased after infection with RSV. Resveratrol increased SARM expression and decreased TRIF expression after RSV infection. SARM knockdown in resveratrol-treated mice enhanced gamma interferon production, RSV-induced airway inflammation, and airway hyperresponsiveness (AHR). Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression. Resveratrol-mediated inhibition of the TRIF-dependent pathway may be dependent on SARM expression. IMPORTANCE Our study provides insights into the regulation of innate immunity in response to RSV infection. The results suggest that resveratrol-mediated alterations in SARM have therapeutic potential against RSV immunopathology caused by deregulation of the TLR-mediated immune response. Ultimately, improved insight into the complex interplay between TLR adaptor proteins and the occurrence of severe RSV infection might lead to novel therapeutic treatment strategies, such as TLR adjuvants.