Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming

• 成果类型: Article
• 署名作者: Lavillegrand, Jean-Remi; Al-Rifai, Rida; Thietart, Sara; Guyon, Theo; 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, Clement; Haub, Jessica; Tedgui, Alain; Speck, Nancy A.; Taleb, Soraya; Mhlanga, Musa M.; Schlitzer, Andreas; Riksen, Niels P.; Ait-Oufella, Hafid
• 署名单位: Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; Sorbonne Universite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Pitie-Salpetriere - APHP; University of Bonn; University of Pennsylvania; University of Pennsylvania; Radboud University Nijmegen; University of Manchester; University of Manchester; Assistance Publique Hopitaux Paris (APHP); Sorbonne Universite; Hopital Universitaire Saint-Antoine - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); AgroParisTech; Universite Paris Saclay; INRAE; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); Helmholtz Association; Helmholtz-Center for Infection Research; University of Wurzburg; Radboud University Nijmegen; Assistance Publique Hopitaux Paris (APHP); Sorbonne Universite; Hopital Universitaire Saint-Antoine - APHP
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4248
• DOI: 10.1038/s41586-024-07693-6
• 发表日期: 2024-10-24
• 关键词: cytokine production; artificial-intelligence; extracellular traps; myelopoiesis; infection; Mutation

摘要

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-1 beta, 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-1 beta pathways abolished emergency myelopoiesis and reversed the pro-atherogenic effects of the alternating HFD. This study highlights the role of IL-1 beta-dependent neutrophil progenitor reprogramming in accelerated atherosclerosis induced by alternating HFD. Re-exposure to a high-fat diet in mice led to emergency myelopoiesis and increased neutrophils in the blood, which infiltrated plaques and released neutrophil extracellular traps, exacerbating atherosclerosis.