Tetrahedral DNA loaded siCCR2 restrains M1 macrophage polarization to ameliorate pulmonary fibrosis in chemoradiation-induced murine model,Molecular Therapy

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Tetrahedral DNA loaded siCCR2 restrains M1 macrophage polarization to ameliorate pulmonary fibrosis in chemoradiation-induced murine model
Molecular Therapy ( IF 12.1 ) Pub Date : 2024-01-24 , DOI: 10.1016/j.ymthe.2024.01.022
Chen Li ₁ , Xiaorong Feng ₁ , Songhang Li ₂ , Xing He ₃ , Zeli Luo ₄ , Xia Cheng ₁ , Jie Yao ₁ , Jie Xiao ₁ , Xiaofei Wang ₅ , Dingke Wen ₆ , Duanya Liu ₁ , Yanfei Li ₇ , Hong Zhou ₈ , Lu Ma ₆ , Tongyu Lin ₁ , Xiaoxiao Cai ₉ , Yunfeng Lin ₉ , Lu Guo ₁₀ , Mu Yang ₁

Affiliation

Centre for Translational Research in Cancer, Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610042, China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
School of Clinical Medicine, Chengdu Medical College, Chengdu 610500, China.
Department of Pulmonary and Critical Care Medicine, Wenjiang Hospital of Sichuan Provincial People's, Chengdu 611138, China.
Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu 610041, China.
School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610056, China.
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China; College of Biomedical Engineering, Sichuan University, Chengdu 610041, China.
Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.

Idiopathic pulmonary fibrosis (IPF) is a chronic lethal disease in the absence of demonstrated efficacy for preventing progression. Although macrophage-mediated alveolitis is determined to participate in myofibrotic transition during disease development, the paradigm of continuous macrophage polarization is still under-explored due to lack of proper animal models. Here, by integrating 2.5 U/kg intratracheal Bleomycin administration and 10 Gy thorax irradiation at day 7, we generated a murine model with continuous alveolitis-mediated fibrosis, which mimics most of the clinical features of our involved IPF patients. In combination with data from scRNA-seq of patients and a murine IPF model, a decisive role of CCL2/CCR2 axis in driving M1 macrophage polarization was revealed, and M1 macrophage was further confirmed to boost alveolitis in leading myofibroblast activation. Multiple sticky-end tetrahedral framework nucleic acids conjunct with quadruple ccr2-siRNA (FNA-siCCR2) was synthesized in targeting M1 macrophages. FNA-siCCR2 successfully blocked macrophage accumulation in pulmonary parenchyma of the IPF murine model, thus preventing myofibroblast activation and leading to the disease remitting. Overall, our studies lay the groundwork to develop a novel IPF murine model, reveal M1 macrophages as potential therapeutic targets, and establish new treatment strategy by using FNA-siCCR2, which are highly relevant to clinical scenarios and translational research in the field of IPF.

中文翻译：

负载四面体 DNA 的 siCCR2 抑制 M1 巨噬细胞极化以改善放化疗诱导的小鼠模型中的肺纤维化

特发性肺纤维化（IPF）是一种慢性致命疾病，目前尚无证据证明其可预防进展。尽管巨噬细胞介导的肺泡炎被确定参与疾病发展过程中的肌纤维化转变，但由于缺乏适当的动物模型，连续巨噬细胞极化的范式仍未得到充分探索。在这里，通过在第 7 天整合 2.5 U/kg 气管内注射博来霉素和 10 Gy 胸部照射，我们生成了具有持续肺泡炎介导的纤维化的小鼠模型，该模型模仿了我们所涉及的 IPF 患者的大多数临床特征。结合患者的 scRNA-seq 数据和小鼠 IPF 模型，揭示了 CCL2/CCR2 轴在驱动 M1 巨噬细胞极化中的决定性作用，并进一步证实 M1 巨噬细胞可促进肺泡炎导致肌成纤维细胞活化。在靶向 M1 巨噬细胞中合成了与四重 ccr2-siRNA (FNA-siCCR2) 结合的多个粘端四面体框架核酸。 FNA-siCCR2成功阻断了IPF小鼠模型肺实质中巨噬细胞的积累，从而阻止了肌成纤维细胞的激活并导致疾病缓解。总体而言，我们的研究为开发新型IPF小鼠模型、揭示M1巨噬细胞作为潜在的治疗靶点以及利用FNA-siCCR2建立新的治疗策略奠定了基础，这与IPF领域的临床情况和转化研究高度相关。

更新日期：2024-01-24

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