Endogenous oxidized phospholipids reprogram cellular metabolism and boost hyperinflammation

Area of Science:

• Immunology
• Metabolic pathways
• Inflammation

Background:

• Pathogen-associated molecular patterns (PAMPs) link inflammatory gene expression to macrophage metabolism.
• Damage-associated molecular patterns (DAMPs) also induce inflammatory gene expression.
• The metabolic impact of DAMPs compared to PAMPs remains largely unknown.

Purpose of the Study:

• To investigate whether DAMPs, specifically oxidized phospholipid oxPAPC, induce similar metabolic shifts in macrophages as PAMPs.
• To determine the role of these metabolic changes in inflammatory responses and disease.

Main Methods:

• Macrophage cultures stimulated with lipopolysaccharide (LPS) and/or oxPAPC.
• Metabolic analysis of glycolysis, mitochondrial respiration, and key metabolite levels.
• In vivo studies in hypercholesterolemic mice and analysis of human subjects.
• Assessment of atherosclerotic plaque formation and drug intervention.

Main Results:

• Macrophages exposed to oxPAPC utilized mitochondrial respiration and glutamine metabolism, unlike LPS-activated cells relying solely on glycolysis.
• OxPAPC promoted oxaloacetate accumulation, enhancing interleukin-1β production and hyperinflammation.
• Similar metabolic adaptations were observed in hypercholesterolemic mice and humans.
• Intervention targeting oxPAPC-driven metabolism reduced atherosclerotic plaque formation in mice.

Conclusions:

• Self-encoded DAMPs like oxPAPC significantly alter macrophage metabolism, contributing to hyperinflammation.
• Metabolic reprogramming by DAMPs is a key driver in inflammatory conditions.
• Targeting DAMP-mediated metabolic pathways offers a potential therapeutic strategy for diseases like atherosclerosis.