L-Arginine Synthesis from L-Citrulline in Myeloid Cells Drives Host Defense against Mycobacteria In Vivo

Shannon M. Lange, Melanie C. McKell, Stephanie M. Schmidt, Junfang Zhao, Rebecca R. Crowther, Lisa C. Green, Rebecca L. Bricker, Eusondia Arnett, S. Eleonore Kohler, Larry S. Schlesinger, Kenneth D. R. Setchell, Joseph E. Qualls*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Web of Science)

Abstract

Immunonutrition as a therapeutic approach is rapidly gaining interest in the fight against infection. Targeting L-arginine metabolism is intriguing, considering this amino acid is the substrate for antimicrobial NO production by macrophages. The importance of L-arginine during infection is supported by the finding that inhibiting its synthesis from its precursor L-citrulline blunts host defense. During the first few weeks following pulmonary mycobacterial infection, we found a drastic increase in L-citrulline in the lung, even though serum concentrations were unaltered. This correlated with increased gene expression of the L-citrulline- generating (i.e., iNOS) and L-citrulline-using (i.e., Ass1) enzymes in key myeloid populations Eliminating L-arginine synthesis from L-citrulline in myeloid cells via conditional deletion of either Ass1 or Asl resulted in increased Mycobacterium bovis bacillus Calmette-Guerin and Mycobacterium tuberculosis H37Rv burden in the lungs compared with controls. Our data illustrate the necessity of L-citrulline metabolism for myeloid defense against mycobacterial infection and highlight the potential for host-directed therapy against mycobacterial disease targeting this nutrient and/or its metabolic pathway.

Original languageEnglish
Pages (from-to)1747-1754
Number of pages8
JournalJournal of Immunology
Volume202
Issue number6
DOIs
Publication statusPublished - 15 Mar 2019

Keywords

  • NITRIC-OXIDE
  • PULMONARY TUBERCULOSIS
  • HEALTHY-SUBJECTS
  • MOUSE MODEL
  • SUPPLEMENTATION
  • AVAILABILITY
  • EXPRESSION
  • SYNTHASE
  • UREA
  • DIFFERENTIATION

Cite this