Macrophages undergo functionally significant reprograming of nucleotide metabolism upon classical activation

Area of Science:

• Immunology
• Metabolic pathways
• Cellular metabolism

Background:

• Macrophage metabolism is critical for immune responses but is primarily studied in central carbon metabolism.
• Limited understanding exists regarding nucleotide metabolism rewiring in activated macrophages.
• Classical macrophage activation necessitates significant metabolic adaptations.

Purpose of the Study:

• To investigate the dynamic changes in nucleotide metabolism during classical macrophage activation.
• To elucidate the molecular mechanisms regulating these metabolic shifts.
• To determine the functional consequences of nucleotide metabolism rewiring for macrophage functions and host-pathogen interactions.

Main Methods:

• Multi-omics analysis to identify significantly altered metabolic pathways.
• Isotopic tracing studies to track metabolic flux and identify key alterations.
• Genetic manipulation (gene knockout) to assess the functional impact of specific metabolic enzymes.

Main Results:

• Classical macrophage activation significantly rewires nucleotide metabolism, shutting down de novo synthesis and increasing salvage pathways.
• Nitric oxide (NO) plays a key role in inhibiting purine and pyrimidine synthesis enzymes (ATIC, CTPS, TYMS).
• Upregulation of degradation enzymes (PNP, UPP) and NO-mediated inhibition of XOR promote nucleotide salvage.
• Knocking out the salvage enzyme hypoxanthine-guanine phosphoribosyl transferase (Hprt) impairs macrophage function and promotes parasite growth.

Conclusions:

• Classically activated macrophages undergo a dynamic shift in nucleotide metabolism, prioritizing salvage over de novo synthesis.
• Nitric oxide and transcriptional regulation are key mechanisms controlling this metabolic reprogramming.
• The rewiring of nucleotide metabolism is essential for proper macrophage function, host defense, and controlling intracellular parasite proliferation.