oxLDL-Induced Trained Immunity Is Dependent on Mitochondrial Metabolic Reprogramming

Area of Science:

• Immunometabolism
• Atherosclerosis research
• Cellular inflammation

Background:

• Monocytes/macrophages can develop long-term pro-inflammatory trained immunity after exposure to oxidized low-density lipoprotein (oxLDL).
• This trained immunity may contribute to the chronic inflammation seen in atherosclerosis.
• Understanding the underlying immunometabolic pathways is crucial for developing targeted therapies.

Purpose of the Study:

• To elucidate the immunometabolic pathways driving trained immunity induced by oxLDL.
• To investigate the role of mitochondrial function and metabolism in oxLDL-trained immunity.

Main Methods:

• Human monocytes were exposed to oxLDL, followed by lipopolysaccharide (LPS) stimulation to assess cytokine production.
• RNA-sequencing and intracellular metabolomics were employed to analyze molecular and metabolic changes.
• Single-cell analysis examined mitochondrial morphology and function.
• Pharmacological inhibitors of oxidative phosphorylation (OXPHOS) and nutrient metabolism were used.
• Genetic variation in OXPHOS-related genes was analyzed in a cohort of healthy subjects.

Main Results:

• Oxidized low-density lipoprotein (oxLDL) exposure led to increased expression of mitochondrial genes and enrichment of tricarboxylic acid (TCA) cycle metabolites.
• Oxidized low-density lipoprotein (oxLDL)-trained macrophages exhibited larger mitochondria and enhanced oxidative phosphorylation (OXPHOS) activity.
• Pharmacological inhibition of OXPHOS, glutamine, and free fatty acid pathways abrogated oxLDL-induced trained immunity.
• Genetic variations in OXPHOS-related genes correlated with the capacity for oxLDL-induced trained immunity in humans.
• Oxidative phosphorylation (OXPHOS) was identified as a key driver of the heightened cytokine response in trained macrophages.

Conclusions:

• Mitochondrial alterations, particularly enhanced oxidative phosphorylation (OXPHOS), are central to oxidized low-density lipoprotein (oxLDL)-induced trained immunity.
• Targeting mitochondrial metabolism, specifically OXPHOS, presents a potential therapeutic strategy to prevent atherosclerosis by modulating trained immunity.