Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming

Jean-Rémi Lavillegrand, Rida Al-Rifai, Sara Thietart, Théo Guyon, Marie Vandestienne, Raphael Cohen, Vincent Duval, Xiaodan Zhong, Daniel Yen, Mumin Ozturk, Yutaka Negishi, Joanne Konkel, Emmanuel Pinteaux, Olivia Lenoir, Jose Vilar, Ludivine Laurans, Bruno Esposito, Marius Bredon, Harry Sokol, Marc Diedisheim, Antoine-Emmanuel Saliba, Alma Zernecke, Clément Cochain, Jessica Haub, Alain Tedgui, Nancy A. Speck, Soraya Taleb, Musa M. Mhlanga, Andreas Schlitzer, Niels P. Riksen and Hafid Ait-Oufella ()
Additional contact information
Jean-Rémi Lavillegrand: Université Paris Cité, INSERM U970
Rida Al-Rifai: Université Paris Cité, INSERM U970
Sara Thietart: Université Paris Cité, INSERM U970
Théo Guyon: Université Paris Cité, INSERM U970
Marie Vandestienne: Université Paris Cité, INSERM U970
Raphael Cohen: Université Paris Cité, INSERM U970
Vincent Duval: Université Paris Cité, INSERM U970
Xiaodan Zhong: Université Paris Cité, INSERM U970
Daniel Yen: University of Pennsylvania
Mumin Ozturk: Radboud University FNWI
Yutaka Negishi: Radboud University FNWI
Joanne Konkel: University of Manchester
Emmanuel Pinteaux: The University of Manchester
Olivia Lenoir: Université Paris Cité, INSERM U970
Jose Vilar: Université Paris Cité, INSERM U970
Ludivine Laurans: Université Paris Cité, INSERM U970
Bruno Esposito: Université Paris Cité, INSERM U970
Marius Bredon: Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital
Harry Sokol: Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint Antoine Hospital
Marc Diedisheim: Clinique Saint Gatien Alliance (NCT+)
Antoine-Emmanuel Saliba: Helmholtz-Center for Infection Research (HZI)
Alma Zernecke: University Hospital Wuerzburg
Clément Cochain: University Hospital Wuerzburg
Jessica Haub: University of Bonn
Alain Tedgui: Université Paris Cité, INSERM U970
Nancy A. Speck: University of Pennsylvania
Soraya Taleb: Université Paris Cité, INSERM U970
Musa M. Mhlanga: Radboud University FNWI
Andreas Schlitzer: University of Bonn
Niels P. Riksen: Radboud University Medical Centre
Hafid Ait-Oufella: Université Paris Cité, INSERM U970

Nature, 2024, vol. 634, issue 8033, 447-456

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07693-6

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