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

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-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.

Tuberculosis causes highly conserved metabolic changes in human patients, mycobacteria-infected mice and zebrafish larvae

“…The only consistently decreased metabolite of these urea cycle intermediates in all three species is citrulline. Interestingly, previous studies have shown that arginine depletion as a result of arginase activity can be replenished from citrulline in macrophages and T-cells and thereby plays a role in immune defense 37,38 . Although in zebrafish larvae, the T-cells are not yet developed 39 , functional macrophages that can express arginase are present 40 .…”

Plasma metabolomics in tuberculosis patients with and without concurrent type 2 diabetes at diagnosis and during antibiotic treatment

“…In mouse models of TB disease, arginase 1 (Arg1) expression in myeloid cells from TB granulomas has been demonstrated to exacerbate disease through substrate competition with NOS 28,29 . Citrulline, however, was shown to fuel antimycobacterial mechanisms of murine macrophages 30,31 and T-cells 32 as an alternative source of intracellular arginine, implying that decreased citrulline levels could be detrimental for TB patients. Although the importance of arginase and NO production for the antimycobacterial response in humans remains controversial, ARG1 was found to be expressed in granulomatous tissue of TB patients 33,34 and could therefore play a role in TB pathophysiology.…”

Macrophage Function in the Pathogenesis of Non-alcoholic Fatty Liver Disease: The Mac Attack

“…As such, studies determining the contribution not only of L-ARG utilization, but also of L-ARG synthesis during NAFLD are warranted. The necessity of L-ARG synthesis within macrophages has recently been described during infection, suggesting extracellular L-ARG is not available in sufficient concentrations to drive effective macrophage function (135,146,147). Accounting for the considerable influx of inflammatory macrophages in NAFLD, future studies aimed at addressing macrophage-specific modulation of L-ARG metabolism with existing molecular tools (e.g., Arg1 flox , Asl flox , Nos2-deficient) (148-150) will be necessary to dissect how various macrophage populations manipulate the liver microenvironment and NAFLD progression.…”