A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

Area of Science:

• Immunology
• Metabolic research
• Cellular biology

Background:

• Metabolic reprogramming is key to immune cell activation.
• The influence of systemic metabolism on immune cell metabolism and function is not well understood.

Purpose of the Study:

• To investigate how dyslipidemia affects immune cell metabolism.
• To characterize the impact of hypercholesterolemia on macrophage metabolism and function.

Main Methods:

• In-depth transcriptional, metabolic, and functional characterization of macrophages.
• Isolation of macrophages from hypercholesterolemic mice.

Main Results:

• Systemic metabolic changes in hypercholesterolemic mice alter macrophage metabolism.
• Maximal mitochondrial respiration is diminished.
• Hypercholesterolemia reduces lipopolysaccharide (LPS)-mediated induction of the pentose phosphate pathway (PPP) and Nrf2 oxidative stress response.
• Suppression of the PPP reduces LPS-induced cytokine secretion.

Conclusions:

• Systemic and cellular metabolism are interconnected.
• Metabolism dictates macrophage phenotype and inflammatory function.
• The PPP is crucial for inflammatory macrophage responses.