Department of Anatomy, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 26426, Republic of Korea.
Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
Int J Mol Sci. 2023 Dec 22;25(1):226. doi: 10.3390/ijms25010226.
Toll-like receptor 3 (TLR3) plays an important role in double-stranded RNA recognition and triggers the innate immune response by acting as a key receptor against viral infections. Intracellular reactive oxygen species (ROS) are involved in TLR3-induced inflammatory responses during viral infections; however, their relationship with mitochondrial ROS (mtROS) remains largely unknown. In this study, we show that polyinosinic-polycytidylic acid (poly(I:C)), a mimic of viral RNA, induced TLR3-mediated nuclear factor-kappa B (NF-B) signaling pathway activation and enhanced mtROS generation, leading to inflammatory cytokine production. TLR3-targeted small interfering RNA (siRNA) and Mito-TEMPO inhibited inflammatory cytokine production in poly(I:C)-treated BEAS-2B cells. Poly(I:C) recruited the TLR3 adaptor molecule Toll/IL-1R domain-containing adaptor, inducing IFN (TRIF) and activated NF-B signaling. Additionally, TLR3-induced mtROS generation suppression and siRNA-mediated TRIF downregulation attenuated mitochondrial antiviral signaling protein (MAVS) degradation. Our findings provide insights into the TLR3-TRIF signaling pathway and MAVS in viral infections, and suggest TLR3-mtROS as a therapeutic target for the treatment of airway inflammatory and viral infectious diseases.
Toll 样受体 3（TLR3）在双链 RNA 识别中发挥重要作用，并通过充当针对病毒感染的关键受体来触发先天免疫反应。细胞内活性氧物种（ROS）参与病毒感染期间 TLR3 诱导的炎症反应；然而，它们与线粒体 ROS（mtROS）的关系在很大程度上尚不清楚。在这项研究中，我们表明，多聚肌苷酸：多聚胞苷酸（poly（I：C）），一种病毒 RNA 的模拟物，诱导 TLR3 介导的核因子-κB（NF-κB）信号通路激活并增强 mtROS 的产生，导致炎症细胞因子的产生。TLR3 靶向的小干扰 RNA（siRNA）和 Mito-TEMPO 抑制了 poly（I：C）处理的 BEAS-2B 细胞中的炎症细胞因子产生。Poly（I：C）募集 TLR3 衔接分子 Toll/IL-1R 域包含衔接蛋白，诱导 IFN（TRIF）并激活 NF-κB 信号。此外，TLR3 诱导的 mtROS 生成抑制和 siRNA 介导的 TRIF 下调减弱了抗病毒信号蛋白（MAVS）的降解。我们的研究结果为 TLR3-TRIF 信号通路和病毒感染中的 MAVS 提供了深入了解，并表明 TLR3-mtROS 可作为治疗气道炎症和病毒性传染病的治疗靶点。
