TY - JOUR
T1 - Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming
AU - Lavillegrand, Jean-Rémi
AU - Al-Rifai, Rida
AU - Thietart, Sara
AU - Guyon, Théo
AU - Vandestienne, Marie
AU - Cohen, Raphael
AU - Duval, Vincent
AU - Zhong, Xiaodan
AU - Yen, Daniel
AU - Ozturk, Mumin
AU - Negishi, Yutaka
AU - Konkel, Joanne
AU - Pinteaux, Emmanuel
AU - Lenoir, Olivia
AU - Vilar, Jose
AU - Laurans, Ludivine
AU - Esposito, Bruno
AU - Bredon, Marius
AU - Sokol, Harry
AU - Diedisheim, Marc
AU - Saliba, Antoine-Emmanuel
AU - Zernecke, Alma
AU - Cochain, Clément
AU - Haub, Jessica
AU - Tedgui, Alain
AU - Speck, Nancy A
AU - Taleb, Soraya
AU - Mhlanga, Musa M
AU - Schlitzer, Andreas
AU - Riksen, Niels P
AU - Ait-Oufella, Hafid
N1 - © 2024. The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2024/10/10
Y1 - 2024/10/10
N2 - 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.
AB - 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.
KW - Animals
KW - Apolipoproteins E/deficiency
KW - Atherosclerosis/metabolism
KW - Bone Marrow Cells/cytology
KW - Cellular Reprogramming
KW - DNA-Binding Proteins/deficiency
KW - Diet, High-Fat/adverse effects
KW - Extracellular Traps
KW - Female
KW - Inflammation/pathology
KW - Interleukin-1beta/metabolism
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Myelopoiesis
KW - Neutrophils/metabolism
KW - Plaque, Atherosclerotic/metabolism
KW - Receptors, LDL/deficiency
KW - Signal Transduction
UR - http://www.scopus.com/inward/record.url?scp=85203178282&partnerID=8YFLogxK
U2 - 10.1038/s41586-024-07693-6
DO - 10.1038/s41586-024-07693-6
M3 - Article
C2 - 39232165
SN - 0028-0836
VL - 634
SP - 447
EP - 456
JO - Nature
JF - Nature
ER -