放射性肺纤维化的新机制：Breg细胞的核心作用

Radiation induced lung fibrosis (RILF) is a common complication of Thoracic radiotherapy, which seriously affects the curative effect and quality of life of the patients. The formation of myofibroblast through epithelial-mesenchymal transition (EMT) is a key factor in the occurrence of RILF, but its detailed mechanisms have not been elucidated. We have found that irradiation induced an increase of TLR9 expression and the proliferation and activation of regulatory B cells (Breg cells), which was related to lung fibrosis. Thus we hypothesized that after recognizing free DNA fragments, up-regulated TLR9 induces the proliferation and activation of Breg cells, and then the activated Breg cells secrete a key effector molecule, e.g. IL-10, to promote the occurrence of EMT, resulting in RILF. The aim of this project is to investigate the mechanism underlying the activation of Breg cells and its regulatory effect on EMT process after lung irradiation, which involves the axis of “irradiation－TLR9-mediated Breg cell proliferation and activation－IL-10/JAK/STAT－EMT”. In this study, we will explore the role of Breg cells in promoting radiation-induced EMT and RILF and the underlying mechanism at animal, cell and molecular levels, respectively. The results that reveal the pathogenesis of RILF from a novel perspective may help with the search of new drug targets for effective prevention and treatment of RILF.

放射性肺纤维化（RILF）是胸部放疗常见并发症，严重影响患者疗效和生活质量。上皮间质转化（EMT）形成肌成纤维细胞是RILF发生的关键因素，但其确切机制尚未阐明。本项目在前期发现照射可导致TLR9表达升高并诱导调节性B细胞（Breg细胞）增殖活化，且与肺纤维化有关的基础上，提出假说：TLR9识别游离DNA片段并介导Breg细胞增殖活化，Breg细胞分泌关键效应分子IL-10促进EMT发生，导致RILF。本项目拟以“照射－TLR9介导Breg增殖活化－IL-10/JAK/STAT－EMT”轴线为切入点，探索肺部受照后Breg细胞增多及其调控EMT的机制。本研究将从动物、细胞及分子各水平上的实验来探讨Breg细胞通过促进EMT发生进而导致RILF的作用及其机制。结果将有利于为该疾病的有效防治寻找新的药物靶点。

放射诱导肺纤维化（RIPF）是胸部肿瘤放疗的严重副作用，但其发病机制尚不清楚。B10细胞作为调节性B细胞（Breg）的亚群，在调节炎症和自身免疫中发挥重要作用。然而，B10细胞在RIPF进展中的作用尚不清楚。本研究的目的是确定B10细胞在辐射诱导的肺纤维化中的作用及其潜在机制。本研究中，我们通过构建放射性肺纤维化小鼠模型发现胸部照射后肺组织中的B10细胞早期显著增加，采用抗CD22抗体消减B10细胞可减轻小鼠RIPF的发展，表明B10细胞可促进RIPF。发现小鼠肺上皮细胞电离辐射可引起细胞凋亡，细胞内DNA以cf-DNA形式释放后与B细胞的TLR9结合及活化，启动其下游信号通路后介导B细胞向B10细胞转化。在体外研究中证实B10细胞可通过激活pSTAT3信号诱导EMT过程和肌成纤维细胞的转化。通过予以阻断IL-10后，证实B10细胞通过分泌的IL-10激活pSTAT3介导EMT及肌成纤维细胞的转化，从而促进RIPF的发生。因此，我们认为B10细胞在促进RIPF的发展中发挥了重要作用，并发现了其可能的机制, 揭示了B10细胞可能是临床上缓解RIPF的新的研究靶点。