Radiotherapy is a commonly used conditioning regimen for bone marrow transplantation (BMT). Cytotoxicity limits the use of this life-saving therapy, but the underlying mechanisms remain poorly defined. Here, we use the syngeneic mouse BMT model to test the hypothesis that lethal radiation damages tissues, thereby unleashing signals that indiscriminately activate the inflammasome pathways in host and transplanted cells. We find that a clinically relevant high dose of radiation causes severe damage to bones and the spleen through mechanisms involving the NLRP3 and AIM2 inflammasomes but not the NLRC4 inflammasome. Downstream, we demonstrate that gasdermin D (GSDMD), the common effector of the inflammasomes, is also activated by radiation. Remarkably, protection against the injury induced by deadly ionizing radiation occurs only when NLRP3, AIM2, or GSDMD is lost simultaneously in both the donor and host cell compartments. Thus, this study reveals a continuum of the actions of lethal radiation relayed by the inflammasome-GSDMD axis, initially affecting recipient cells and ultimately harming transplanted cells as they grow in the severely injured and toxic environment. This study also suggests that therapeutic targeting of inflammasome-GSDMD signaling has the potential to prevent the collateral effects of intense radiation regimens.

放疗是骨髓移植 (BMT) 常用的预处理方案。细胞毒性限制了这种挽救生命的疗法的使用，但其潜在机制仍不清楚。在这里，我们使用同基因小鼠 BMT 模型来检验致命辐射损伤组织的假设，从而释放不加选择地激活宿主和移植细胞中的炎性体通路的信号。我们发现临床相关的高剂量辐射会通过涉及 NLRP3 和 AIM2 炎症小体而非 NLRC4 炎症小体的机制对骨骼和脾脏造成严重损伤。在下游，我们证明了炎症小体的常见效应物 gasdermin D (GSDMD) 也被辐射激活。值得注意的是，只有当 NLRP3、AIM2、或 GSDMD 在供体和宿主细胞区室中同时丢失。因此，这项研究揭示了由炎性体-GSDMD 轴传递的致死辐射作用的连续统一体，最初影响受体细胞，最终伤害移植细胞，因为它们在严重受伤和有毒的环境中生长。这项研究还表明，炎症小体-GSDMD 信号的治疗靶向有可能预防强烈放射方案的附带影响。