1 School of Medicine and Medical Science, College of Life Sciences, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin, Ireland.
Am J Respir Crit Care Med. 2013 Dec 15;188(12):1442-50. doi: 10.1164/rccm.201304-0760OC.
Idiopathic pulmonary fibrosis (IPF) is a fatal progressive interstitial pneumonia. The innate immune system provides a crucial function in the recognition of tissue injury and infection. Toll-like receptor 3 (TLR3) is an innate immune system receptor. We investigated the role of a functional TLR3 single-nucleotide polymorphism in IPF.
To characterize the effects of the TLR3 Leu412Phe polymorphism in primary pulmonary fibroblasts from patients with IPF and disease progression in two independent IPF patient cohorts. To investigate the role of TLR3 in a murine model of pulmonary fibrosis.
TLR3-mediated cytokine, type 1 IFN, and fibroproliferative responses were examined in TLR3 wild-type (Leu/Leu), heterozygote (Leu/Phe), and homozygote (Phe/Phe) primary IPF pulmonary fibroblasts by ELISA, real-time polymerase chain reaction, and proliferation assays. A murine model of bleomycin-induced pulmonary fibrosis was used in TLR3 wild-type (tlr3(+/+)) and TLR3 knockout mice (tlr3(-/-)). A genotyping approach was used to investigate the role of the TLR3 L412F polymorphism in disease progression in IPF using survival analysis and longitudinal decline in FVC.
Activation of TLR3 in primary lung fibroblasts from TLR3 L412F-variant patients with IPF resulted in defective cytokine, type I IFN, and fibroproliferative responses. We demonstrate increased collagen and profibrotic cytokines in TLR3 knockout mice (tlr3(-/-)) compared with wild-type mice (tlr3(+/+)). TLR3 L412F was also associated with a significantly greater risk of mortality and an accelerated decline in FVC in patients with IPF.
This study reveals the crucial role of defective TLR3 function in promoting progressive IPF.
特发性肺纤维化（IPF）是一种致命的进行性间质性肺炎。先天免疫系统在识别组织损伤和感染方面起着至关重要的作用。Toll 样受体 3（TLR3）是先天免疫系统的受体。我们研究了功能性 TLR3 单核苷酸多态性在 IPF 中的作用。
在特发性肺纤维化患者的原代肺成纤维细胞中，研究 TLR3 Leu412Phe 多态性在两个独立的特发性肺纤维化患者队列中的作用及疾病进展。研究 TLR3 在肺纤维化小鼠模型中的作用。
通过 ELISA、实时聚合酶链反应和增殖试验，检测 TLR3 野生型（Leu/Leu）、杂合型（Leu/Phe）和纯合型（Phe/Phe）特发性肺纤维化患者原代肺成纤维细胞中 TLR3 介导的细胞因子、I 型干扰素和纤维增生反应。采用博莱霉素诱导的肺纤维化小鼠模型，研究 TLR3 野生型（tlr3(+/+))和 TLR3 敲除小鼠（tlr3(-/-))。采用基因分型方法，通过生存分析和 FVC 纵向下降，研究 TLR3 L412F 多态性在特发性肺纤维化疾病进展中的作用。
在 TLR3 L412F 变体的特发性肺纤维化患者的原代肺成纤维细胞中，TLR3 的激活导致细胞因子、I 型干扰素和纤维增生反应缺陷。与野生型小鼠（tlr3(+/+))相比，我们发现 TLR3 敲除小鼠（tlr3(-/-))中胶原和促纤维化细胞因子增加。TLR3 L412F 也与特发性肺纤维化患者的死亡率显著增加和 FVC 下降加速相关。
本研究揭示了 TLR3 功能缺陷在促进进行性特发性肺纤维化中的关键作用。
