放射线诱导的肺损伤（RILI）是癌症患者胸部放疗常见的并发症。对RILI潜在机制的全面理解对于开发有效的预防和治疗策略至关重要。为了研究RILI，我们利用了接受12.5 Gy整体胸部照射的小鼠模型。通过定量实时聚合酶链反应（qRT-PCR）、酶联免疫吸附检测法（ELISA）、组织学、免疫组织化学、Western blot、RNA测序和流式细胞术的组合进行了RILI的评估。此外，我们建立了一个由巨噬细胞、肺上皮细胞和成纤维细胞组成的胞外培养系统用于体外研究。在该系统中，肺上皮细胞接受了4 Gy剂量的照射，并采用STING基因敲除的巨噬细胞。进行了转化检查以探索术前肺组织中STING表达、循环CCL2动态变化和RILI发展之间的关系。我们的研究结果显示，在受到放射线照射的小鼠肺中，cGAS-STING途径显著激活，并且巨噬细胞M1极化。体外研究表明cGAS-STING信号通路缺陷导致巨噬细胞极化和RILI受损。通过RNA测序、细胞因子分析和使用CCL2抑制剂Bindarit进行救治实验，我们确定了CCL2参与了巨噬细胞极化和RILI发展的调控。此外，使用胸部放疗前后收集的患者样本进行的转化研究提供了额外的证据，支持cGAS-STING信号活性、CCL2上调与放射性肺炎发展之间的关联。cGAS-STING信号通路在RILI发病过程中通过CCL2在调控巨噬细胞的招募和极化中起关键作用。© 2023年，BioMed Central有限公司，为Springer Nature的一部分。

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic radiotherapy in cancer patients. A comprehensive understanding of the underlying mechanisms of RILI is essential for the development of effective prevention and treatment strategies.To investigate RILI, we utilized a mouse model that received 12.5 Gy whole-thoracic irradiation. The evaluation of RILI was performed using a combination of quantitative real-time polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), histology, western blot, immunohistochemistry, RNA sequencing, and flow cytometry. Additionally, we established a co-culture system consisting of macrophages, lung epithelial cells, and fibroblasts for in vitro studies. In this system, lung epithelial cells were irradiated with a dose of 4 Gy, and we employed STING knockout macrophages. Translational examinations were conducted to explore the relationship between STING expression in pre-radiotherapy lung tissues, dynamic changes in circulating CCL2, and the development of RILI.Our findings revealed significant activation of the cGAS-STING pathway and M1 polarization of macrophages in the lungs of irradiated mice. In vitro studies demonstrated that the deficiency of cGAS-STING signaling led to impaired macrophage polarization and RILI. Through RNA sequencing, cytokine profiling, and rescue experiments using a CCL2 inhibitor called Bindarit, we identified the involvement of CCL2 in the regulation of macrophage polarization and the development of RILI. Moreover, translational investigations using patient samples collected before and after thoracic radiotherapy provided additional evidence supporting the association between cGAS-STING signaling activity, CCL2 upregulation, and the development of radiation pneumonitis.The cGAS-STING signaling pathway plays a crucial role in regulating the recruitment and polarization of macrophages, partly through CCL2, during the pathogenesis of RILI.© 2023. BioMed Central Ltd., part of Springer Nature.