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

• Published in: The Journal of immunology (1950) Vol. 202; no. 6; pp. 1747 - 1754
• Main Authors: Lange, Shannon M, McKell, Melanie C, Schmidt, Stephanie M, Zhao, Junfang, Crowther, Rebecca R, Green, Lisa C, Bricker, Rebecca L, Arnett, Eusondia, Köhler, S Eleonore, Schlesinger, Larry S, Setchell, Kenneth D R, Qualls, Joseph E
• Format: Journal Article
• Language: English
• Published: United States 15.03.2019
• Subjects: Animals; Arginine - immunology; Arginine - metabolism; Citrulline - immunology; Citrulline - metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mycobacterium Infections - immunology; Mycobacterium Infections - metabolism; Myeloid Cells - immunology; Myeloid Cells - metabolism; Respiratory Tract Infections - immunology; Respiratory Tract Infections - metabolism
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1801569

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-Guérin 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.