Paris Cardiovascular Research Center, Université Paris Cité, INSERM U970, Paris, France.
Geriatrics Department, Sorbonne Université, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié Salpêtrière, Paris, France.
Nature. 2024 Oct;634(8033):447-456. doi: 10.1038/s41586-024-07693-6. Epub 2024 Sep 4.
Systemic immune responses caused by chronic hypercholesterolaemia contribute to atherosclerosis initiation, progression and complications. However, individuals often change their dietary habits over time, 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 ApoeRag2 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 RUNX1, 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系统性免疫反应导致动脉粥样硬化的发生、发展和并发症。然而，个体通常会随着时间的推移改变他们的饮食习惯，交替高脂肪饮食（HFD）对动脉粥样硬化的影响尚不清楚。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，比较了交替与连续 HFD ，同时保持相似的总暴露期。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。这种交替 HFD 的促动脉粥样硬化作用也在缺乏 T、B 和自然杀伤 T 细胞的 ApoeRag2 小鼠中观察到，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 饮食下调了 RUNX1，促进了骨髓髓系祖细胞中的炎症信号。在重新暴露于 HFD 后，这些细胞产生了 IL-1β，导致紧急髓样生成和血液中中性粒细胞水平增加。中性粒细胞浸润斑块并释放中性粒细胞细胞外陷阱，加剧动脉粥样硬化。中性粒细胞的特异性耗竭或 IL-1β 途径的抑制消除了紧急髓样生成，并逆转了交替 HFD 的促动脉粥样硬化作用。这项研究强调了 IL-1β 依赖性中性粒细胞祖细胞重编程在交替 HFD 诱导的加速动脉粥样硬化中的作用。
