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Series GSE254105 Query DataSets for GSE254105
Status Public on Apr 23, 2024
Title Alternate high fat diet aggravates atherosclerosis through an IL1B- 2 dependent reprogramming of neutrophil progenitors
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Systemic immune responses induced by chronic hypercholesterolemia contribute to the initiation, progression and complications of atherosclerosis. However, it is common for individuals to change dietary habits over time. The consequences of an alternating high fat diet and the associated variations in plasma cholesterol levels on atherosclerosis are unknown. To address this relevant issue, we developed a novel protocol in atherosclerosis-prone mice that allowed us to compare the effects of alternate versus continuous high fat diet (HFD) on atherosclerosis, while keeping the overall period of exposure to HFD similar between groups. We showed that an alternate HFD lead to accelerated atherosclerosis in Ldlr-/- and Apoe 55 -/- mice compared to continuous HFD. This pro-atherogenic effect of alternate HFD was also observed in Apoe-/-Rag2 57 -/- mice lacking T, B, and NKT cells, ruling out the role of the adaptive immune system in the observed phenotype. Employing various complementary in vivo approaches, we discovered that discontinuing HFD in the alternate group downregulated Runx1, a negative regulator of inflammatory signaling pathways in the myeloid lineage. Consequently, after re61 exposure to HFD, myeloid progenitors were primed to respond to HFD re-exposure by differentiating into IL-1-producing immature neutrophils, and inducing a state of emergency myelopoiesis. Subsequently, neutrophils markedly increased in the peripheral blood, infiltrated atherosclerotic lesions and locally released neutrophil extracellular traps. Anti-Ly6G neutrophil depletion abolished the pro-atherogenic effects of alternate HFD. Specific deletion of Il1b and Il1 receptor confirmed that the IL-1 signaling pathway was a major driver of the pro67 inflammatory and pro-atherogenic neutrophil signature. Finally, treatment with anti-IL-1 neutralizing antibody or an inflammasome inhibitor during re-exposure to HFD reversed the pro-atherogenic effects of alternate HFD. In summary, we showed that alternate HFD accelerates atherosclerosis through IL-1-dependent neutrophil progenitor reprogramming.
Overall design To investigate the impact of hypercholesterolemia re-exposure on atherosclerosis, we developed a protocol with 2 different diet regimens. One group of 6-week old female Ldlr-/- 360 mice was put on a so-called “alternate” HFD consisting of a first period of 4 weeks of HFD, followed by 8 weeks of regular chow diet, and then a final 4-weeks of HFD. The control group was fed a so-called “continuous” HFD during the last 8 weeks of the protocol
Contributor(s) Lavillegrand J, Diedisheim M, Ait-Oufella H
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Submission date Jan 24, 2024
Last update date Apr 24, 2024
Contact name Hafid Ait-Oufella
Phone +33612011940
Organization name Inserm
Department U970
Street address 56, Rue Leblanc
City Paris
ZIP/Postal code 75015
Country France
Platforms (1)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (10)
GSM8033413 s75934
GSM8033414 s75935
GSM8033415 s76002
BioProject PRJNA1068574

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Supplementary file Size Download File type/resource
GSE254105_RAW.tar 11.0 Mb (http)(custom) TAR (of RESULTS)
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Raw data are available in SRA

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