Trujillo Glenda, Regueiro-Ren Alicia, Liu Chunjian, Hu Buqu, Sun Ying, Ahangari Farida, Fiorini Vitoria, Ishikawa Genta, Al Jumaily Karam, Khoury Johad, McGovern John, Lee Chris J, Peng Xue Yan, Pivarnik Taylor, Sun Huanxing, Walia Anjali, Woo Samuel, Yu Sheeline, Antin-Ozerkis Danielle E, Sauler Maor, Kaminski Naftali, Herzog Erica L, Ryu Changwan
Bristol-Myers Squibb Company, New York, New York, United States.
Yale School of Medicine, New Haven, Connecticut, United States.
Am J Respir Crit Care Med. 2024 Aug 27;211(1):91-102. doi: 10.1164/rccm.202401-0065OC.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA).
We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor.
We employed two independent cohorts of patients with IPF, multiple fibroblast cell culture platforms, an mouse model, and an human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease.
In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFβ1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our and models of pulmonary fibrosis.
In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.
特发性肺纤维化（IPF）是一种致命的肺部疾病，目前的治疗方案只能减缓临床进展。此前，我们发现一部分IPF患者疾病进程加速，这与成纤维细胞通过与配体线粒体DNA（mtDNA）相互作用介导的Toll样受体9（TLR9）表达有关。
我们旨在通过使用两种市售间接抑制剂和一种专利选择性直接小分子抑制剂，证明TLR9激活可诱导成纤维细胞增殖反应，而其拮抗作用可消除这种反应。
我们采用两组独立的IPF患者队列、多个成纤维细胞培养平台、一个小鼠模型和一个人精密肺切片系统，来研究TLR9在该疾病中的临床和生物学意义。
在两组独立的IPF队列中，血浆mtDNA以与单核细胞趋化蛋白-1（MCP-1）、白细胞介素-6（IL-6）、肿瘤坏死因子α（TNFα）和干扰素γ诱导蛋白10（IP-10）表达相关的方式激活TLR9，并使无移植生存期恶化。我们的细胞培养平台表明，TLR9通过转化生长因子β1（TGFβ1）和坚硬底物介导成纤维细胞活化，其拮抗作用，尤其是直接抑制作用，可改善这一过程，包括这些与TLR9相关的药效学终点的产生。我们进一步证明，直接抑制TLR9可减轻我们的肺纤维化小鼠模型和人精密肺切片模型中的这些成纤维细胞增殖反应。
在这项新研究中，我们发现直接抑制TLR9可减轻肺纤维化临床前模型中的成纤维细胞增殖反应。我们的工作证明了直接拮抗TLR9在IPF和相关纤维化肺病中的治疗潜力。
