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Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1

Joseph E Qualls1, Chitra Subramanian, Wasiulla Rafi

  • 1Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Cell Host & Microbe
|September 18, 2012
PubMed

Insights

Macrophages use arginine to produce nitric oxide (NO) against pathogens. Citrulline export initially fuels NO, while later recycling via Ass1 and Asl sustains production when arginine is scarce.

Area of Science:

  • Immunology
  • Cellular Metabolism
  • Biochemistry

Background:

  • Nitric oxide (NO) is crucial for innate immunity against intracellular pathogens.
  • Macrophage NO synthesis relies on arginine, producing citrulline as a byproduct.
  • Intracellular citrulline was hypothesized to support sustained NO production via the argininosuccinate synthase (Ass1) and argininosuccinate lyase (Asl) pathway.

Purpose of the Study:

  • To investigate the metabolic fate of citrulline during macrophage NO production.
  • To determine the role of the Ass1-Asl pathway in sustaining NO synthesis under varying arginine availability.

Main Methods:

  • Macrophage cell cultures
  • Measurement of nitric oxide production
  • Analysis of intracellular and extracellular metabolite levels
  • Assessment of Ass1 and Asl expression and activity

Main Results:

  • Citrulline is primarily exported from macrophages during early NO production.
  • Only a small fraction (<2%) of citrulline is retained for recycling via Ass1-Asl.
  • Ass1 expression enables arginine synthesis from imported citrulline when extracellular arginine is depleted, sustaining NO output.
  • Ass1-deficient macrophages exhibit impaired control of mycobacteria infection due to insufficient NO production.

Conclusions:

  • Extracellular arginine is the primary source for rapid NO production in activated macrophages.
  • Citrulline recycling through the Ass1-Asl pathway acts as a critical fail-safe mechanism to maintain NO production.
  • This pathway is essential for sustained macrophage antimicrobial function, particularly in arginine-limited environments.

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