Alternating high-fat diet enhances atherosclerosis by neutrophil reprogramming

Area of Science:

• Cardiovascular Research
• Immunology
• Metabolic Disorders

Background:

• Chronic hypercholesterolemia drives atherosclerosis through systemic immune responses.
• Dietary habits fluctuate, yet the impact of alternating high-fat diets (HFD) on atherosclerosis is not well understood.

Purpose of the Study:

• To investigate the effects of an alternating HFD compared to a continuous HFD on atherosclerosis development.
• To elucidate the underlying immune mechanisms driving accelerated atherosclerosis under alternating HFD conditions.

Main Methods:

• Atherosclerosis-prone mice (Ldlr-/- and Apoe-/-) were subjected to alternating or continuous HFD protocols with similar overall exposure.
• Experiments included immunodeficient mice (Apoe-/-Rag2-/-) to assess the role of adaptive immunity.
• Key molecular pathways (RUNX1, IL-1β) and cellular components (neutrophils) were analyzed.

Main Results:

• Alternating HFD significantly accelerated atherosclerosis compared to continuous HFD in susceptible mouse models.
• The pro-atherogenic effect was independent of adaptive immunity (T, B, NK T cells).
• Alternating HFD induced RUNX1 downregulation, promoting IL-1β production and emergency myelopoiesis, leading to increased blood neutrophils that infiltrated plaques.

Conclusions:

• Alternating HFD exacerbates atherosclerosis through an IL-1β-dependent mechanism involving emergency myelopoiesis and neutrophil activation.
• Targeting IL-1β or neutrophils can reverse the pro-atherogenic effects of alternating HFD, suggesting potential therapeutic strategies.