Leibowitz Brian J, Zhao Guangyi, Wei Liang, Ruan Hang, Epperly Michael, Chen Lujia, Lu Xinghua, Greenberger Joel S, Zhang Lin, Yu Jian
Department of Pathology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Department of Radiation Oncology, University of Pittsburgh School of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15213, USA.
Sci Adv. 2021 Oct 8;7(41):eabi5253. doi: 10.1126/sciadv.abi5253. Epub 2021 Oct 6.
The cGAS-STING cytosolic DNA sensing pathway is critical for host defense. Here, we report that cGAS-STING–dependent type 1 interferon (IFN) response drives intestinal regeneration and animal recovery from radiation injury. deficiency has no effect on radiation-induced DNA damage or crypt apoptosis but abrogates epithelial IFN-β production, local inflammation, innate transcriptional response, and subsequent crypt regeneration. KO, KO, or KO also abrogates radiation-induced acute crypt inflammation and regeneration. Impaired intestinal regeneration and survival in deficient mice are fully rescued by a single IFN-β treatment given 48 hours after irradiation but not by wild-type (WT) bone marrow. IFN-β treatment remarkably improves the survival of WT mice and Lgr5 stem cell regeneration through elevated compensatory proliferation and more rapid DNA damage removal. Our findings support that inducible IFN-β production in the niche couples ISC injury and regeneration and its potential use to treat acute radiation injury.
cGAS-STING胞质DNA感应通路对宿主防御至关重要。在此，我们报道依赖cGAS-STING的1型干扰素（IFN）反应驱动肠道再生以及动物从辐射损伤中恢复。cGAS缺陷对辐射诱导的DNA损伤或隐窝凋亡没有影响，但会消除上皮细胞IFN-β的产生、局部炎症、固有转录反应以及随后的隐窝再生。cGAS基因敲除（KO）、STING基因敲除或TBK1基因敲除也会消除辐射诱导的急性隐窝炎症和再生。照射后48小时给予单次IFN-β治疗可完全挽救cGAS缺陷小鼠肠道再生和生存能力受损的情况，但野生型（WT）骨髓无法起到这种作用。IFN-β治疗通过提高代偿性增殖和更快速地清除DNA损伤，显著提高WT小鼠的生存率和Lgr5干细胞再生能力。我们的研究结果支持在特定微环境中诱导产生的IFN-β将肠干细胞（ISC）损伤与再生联系起来，以及其在治疗急性辐射损伤方面的潜在用途。
