Radiation is associated with tissue damage and increased risk of atherosclerosis, but there are currently no treatments and a very limited mechanistic understanding of how radiation impacts tissue repair mechanisms. We uncovered that radiation significantly delayed temporal resolution programs that were associated with decreased efferocytosis in vivo. Resolvin D1 (RvD1), a known proresolving ligand, promoted swift resolution and restored efferocytosis in sublethally irradiated mice. Irradiated macrophages exhibited several features of senescence, including increased expression of p16^INK4A and p21, heightened levels of SA-β-gal, COX-2, several proinflammatory cytokines/chemokines, and oxidative stress (OS) in vitro, and when transferred to mice, they exacerbated inflammation in vivo. Mechanistically, heightened OS in senescent macrophages led to impairment in their ability to carry out efficient efferocytosis, and treatment with RvD1 reduced OS and improved efferocytosis. Sublethally irradiated Ldlr^−/− mice exhibited increased plaque necrosis, p16^INK4A cells, and decreased lesional collagen compared with nonirradiated controls, and treatment with RvD1 significantly reduced necrosis and increased lesional collagen. Removal of p16^INK4A hematopoietic cells during advanced atherosclerosis with p16-3MR mice reduced plaque necrosis and increased production of key intraplaque-resolving mediators. Our results demonstrate that sublethal radiation drives macrophage senescence and efferocytosis defects and suggest that RvD1 may be a new therapeutic strategy to limit radiation-induced tissue damage.

辐射与组织损伤和动脉粥样硬化风险增加有关，但目前尚无治疗方法，对辐射如何影响组织修复机制的机制理解非常有限。我们发现辐射显着延迟了与体内 efferocytosis 减少相关的时间分辨率程序。Resolvin D1 (RvD1) 是一种已知的促分解配体，可促进亚致死照射小鼠的快速分解并恢复细胞增多症。辐照巨噬细胞表现出多种衰老特征，包括 p16 ^{INK4A表达增加}和 p21，SA-β-gal、COX-2、几种促炎细胞因子/趋化因子和体外氧化应激 (OS) 水平升高，当转移到小鼠体内时，它们会加剧体内炎症。从机制上讲，衰老巨噬细胞中 OS 的升高会导致它们进行有效细胞增多症的能力受损，而用 RvD1 治疗会降低 OS 并改善细胞增多症。与未照射的对照组相比，亚致死照射的 Ldlr ^-/-小鼠表现出增加的斑块坏死、p16 ^INK4A细胞和减少的损伤胶原蛋白，并且用 RvD1 治疗显着减少了坏死并增加了损伤胶原蛋白。去除 p16 ^INK4Ap16-3MR 小鼠在晚期动脉粥样硬化期间的造血细胞减少了斑块坏死并增加了关键斑块内解决介质的产生。我们的研究结果表明，亚致死辐射驱动巨噬细胞衰老和细胞增多症缺陷，并表明 RvD1 可能是一种限制辐射引起的组织损伤的新治疗策略。