Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
Department of Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, 222000, China.
Cancer Lett. 2024 Nov 1;604:217218. doi: 10.1016/j.canlet.2024.217218. Epub 2024 Sep 2.
Ionizing radiation (IR)-induced intestinal injury remains a major limiting factor in abdominal radiation therapy, and its pathogenesis remains unclear. In this study, mouse models of IR-induced intestinal injury were established, and the effect of IR on nuclear factor erythroid 2-related factor 2 (Nrf2) was determined. More severe IR-induced intestinal damage was observed in Nrf2 knockout (KO) mice than in wild-type mice. Then, the negative regulation of cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling by Nrf2 was examined both in vivo and in vitro after IR. This was accompanied by alterations in the intestinal neutrophil and macrophage populations in mice. Subsequently, the effect of the cGAS/STING pathway on the intestinal toxicity of IR was also investigated. Moreover, the downregulation of cGAS/STING by Nrf2 via its target gene, Pirin, was confirmed using transfection assays. A rescue experiment with Pirin was also conducted using adeno-associated virus in Nrf2 KO mice. Finally, the protective effect of calcitriol against IR-induced intestinal injury, along with increased Nrf2 and Pirin levels and decreased cGAS, pSTING, and interferon-beta levels, were observed. Taken together, our results suggest that Nrf2 alleviates IR-induced intestinal injury through Pirin-mediated inhibition of the innate immunity-related cGAS/STING pathway.
电离辐射（IR）诱导的肠道损伤仍然是腹部放射治疗的主要限制因素，其发病机制尚不清楚。在本研究中，建立了 IR 诱导的肠道损伤小鼠模型，并确定了 IR 对核因子红细胞 2 相关因子 2（Nrf2）的影响。与野生型小鼠相比，Nrf2 敲除（KO）小鼠中观察到更严重的 IR 诱导的肠道损伤。然后，在体内和体外检查了 Nrf2 对 IR 后环鸟苷酸-腺苷酸合酶/干扰素基因刺激物（cGAS/STING）信号的负调控作用。这伴随着小鼠肠道中性粒细胞和巨噬细胞群体的改变。随后，还研究了 cGAS/STING 途径对 IR 肠道毒性的影响。此外，还通过转染实验证实了 Nrf2 通过其靶基因 Pirin 对 cGAS/STING 的下调作用。还使用腺相关病毒在 Nrf2 KO 小鼠中进行了 Pirin 的挽救实验。最后，观察到骨化三醇对 IR 诱导的肠道损伤的保护作用，同时 Nrf2 和 Pirin 水平增加，cGAS、pSTING 和干扰素-β水平降低。总之，我们的研究结果表明，Nrf2 通过 Pirin 介导的抑制先天免疫相关的 cGAS/STING 途径来减轻 IR 诱导的肠道损伤。
