Systemic immune responses caused by chronic hypercholesterolaemia contribute to atherosclerosis initiation, progression and complications¹. However, individuals often change their dietary habits over time², and the effects of an alternating high-fat diet (HFD) on atherosclerosis remain unclear. Here, to address this relevant issue, we developed a protocol using atherosclerosis-prone mice to compare an alternating versus continuous HFD while maintaining similar overall exposure periods. We found that an alternating HFD accelerated atherosclerosis in Ldlr^−/− and Apoe^−/− mice compared with a continuous HFD. This pro-atherogenic effect of the alternating HFD was also observed in Apoe^−/−Rag2^−/− mice lacking T, B and natural killer T cells, ruling out the role of the adaptive immune system in the observed phenotype. Discontinuing the HFD in the alternating HFD group downregulated RUNX1³, promoting inflammatory signalling in bone marrow myeloid progenitors. After re-exposure to an HFD, these cells produced IL-1β, leading to emergency myelopoiesis and increased neutrophil levels in blood. Neutrophils infiltrated plaques and released neutrophil extracellular traps, exacerbating atherosclerosis. Specific depletion of neutrophils or inhibition of IL-1β pathways abolished emergency myelopoiesis and reversed the pro-atherogenic effects of the alternating HFD. This study highlights the role of IL-1β-dependent neutrophil progenitor reprogramming in accelerated atherosclerosis induced by alternating HFD.

慢性高胆固醇血症引起的全身免疫反应会导致动脉粥样硬化的发生、进展和并发症¹。然而，随着时间的推移，个体通常会改变他们的饮食习惯²，交替高脂饮食 （HFD） 对动脉粥样硬化的影响仍不清楚。在这里，为了解决这个相关问题，我们开发了一种使用易患动脉粥样硬化的小鼠的方案来比较交替与连续 HFD，同时保持相似的整体暴露期。我们发现，与连续 HFD 相比，交替 HFD 加速了 Ldlr^-/-和 Apoe^-/-小鼠的动脉粥样硬化。在缺乏 T、B 和自然杀伤 T 细胞的 Apoe^-/-Rag2^-/-小鼠中也观察到交替 HFD 的这种促动脉粥样硬化作用，排除了适应性免疫系统在观察到的表型中的作用。在交替 HFD 组中停止 HFD 下调了 RUNX1³，促进了骨髓祖细胞中的炎症信号传导。再次暴露于 HFD 后，这些细胞产生 IL-1β，导致紧急骨髓生成和血液中中性粒细胞水平升高。中性粒细胞浸润斑块并释放中性粒细胞胞外陷阱，加剧动脉粥样硬化。中性粒细胞的特异性耗竭或 IL-1β 通路的抑制消除了紧急骨髓生成并逆转了交替 HFD 的促动脉粥样硬化作用。本研究强调了 IL-1β 依赖性中性粒细胞祖细胞重编程在交替性 HFD 诱导的加速动脉粥样硬化中的作用。