Radiation Adaptive Response Enhances Hematopoietic Stem and Progenitor Cells Radioresistance in Mice: IL-17 Signaling Pathway Activation as the Underlying Mechanism

Radiation adaptive response (RAR) significantly improves resistance to subsequent high-dose radiation exposure. While hematopoietic stem and progenitor cells (HSPCs) are known to be crucial for radiation protection, their specific roles and response mechanisms in RAR remain unclear. Systematic investigation of these processes could reveal valuable therapeutic targets for developing HSPCs-focused radiation protection strategies. We establish a radiation-adaptive mouse model by administering a priming dose of 0.5 Gy γ rays after a 14-day interval and then investigate the protective effects and underlying mechanisms of RAR on HSPCs. Our results demonstrate that 0.5 Gy pre-irradiation significantly enhances the radioresistance of HSPCs against subsequent 6.5 Gy irradiation, attenuates the radiation-induced suppression of both HSPCs quantity and repopulation capacity, and consequently facilitating the restoration of hematopoiesis. Additionally, 0.5 Gy irradiation alone increases the DNA damage and apoptosis of HPCs and LSKs, which in turn activates dormant HSCs but attenuates their long-term repopulating capability. Notably, 0.5 Gy irradiation activates the IL-17 signaling pathway in LSKs and upregulates IL-17A expression in both plasma and jejunum. Neutralization of IL-17A not only abrogates the RAR induced by 0.5 Gy pre-irradiation but also attenuates the protective effect of this pre-irradiation on HSPCs. This study systematically elucidates the radioprotective effects of RAR on mouse bone marrow cell subsets, unveils the important potential role of the IL-17 signaling pathway in RAR, and provides new insights into the underlying mechanisms of radiation-adaptive protection. It also provides theoretical support for the development of targeted intervention strategies in radiation protection for HSPCs.