交替高脂饮食通过中性粒细胞重编程促进动脉粥样硬化，这一成果由法国巴黎城市大学Hafid Ait-Oufella等合作小组经过不懈努力而取得。该项研究成果发表在2024年9月4日出版的《自然》上。

课题组研究人员制定了一项使用动脉粥样硬化易感小鼠的实验方案，在保持相似的总暴露时间的情况下，比较交替和连续高脂肪饮食(HFD)。小组发现，与连续的高脂肪饮食相比，交替的高脂肪饮食加速了Ldlr^-/-和Apoe^-/-小鼠动脉粥样硬化作用。

这种交替性高脂肪饮食对动脉粥样硬化的促进作用同样在缺乏T细胞、B细胞和天然杀伤T细胞的Apoe^-/-Rag2^-/-小鼠中观察到，从而排除了适应性免疫系统在观察到的表型中所起的作用。

交替高脂肪饮食组停用高脂肪饮食可下调RUNX1，促进骨髓祖细胞的炎症信号传导。在再次暴露于高脂肪饮食后，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，加重动脉粥样硬化。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，逆转了交替高脂肪饮食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高脂肪饮食诱导的加速动脉粥样硬化中的作用。

据悉，慢性高胆固醇血症引发的全身免疫反应有助于动脉粥样硬化的发生、进展和并发症。然而，随着时间的推移，人们经常改变他们的饮食习惯，而交替高脂肪饮食(HFD)对动脉粥样硬化的影响尚不清楚。

附：英文原文

Title: Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming

Author: Lavillegrand, Jean-Rmi, Al-Rifai, Rida, Thietart, Sara, Guyon, Tho, Vandestienne, Marie, Cohen, Raphael, Duval, Vincent, Zhong, Xiaodan, Yen, Daniel, Ozturk, Mumin, Negishi, Yutaka, Konkel, Joanne, Pinteaux, Emmanuel, Lenoir, Olivia, Vilar, Jose, Laurans, Ludivine, Esposito, Bruno, Bredon, Marius, Sokol, Harry, Diedisheim, Marc, Saliba, Antoine-Emmanuel, Zernecke, Alma, Cochain, Clment, Haub, Jessica, Tedgui, Alain, Speck, Nancy A., Taleb, Soraya, Mhlanga, Musa M., Schlitzer, Andreas, Riksen, Niels P., Ait-Oufella, Hafid

Issue&Volume: 2024-09-04

Abstract: 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.

DOI: 10.1038/s41586-024-07693-6

Source: https://www.nature.com/articles/s41586-024-07693-6