l-Arginine Uptake by Cationic Amino Acid Transporter Promotes Intra-Macrophage Survival of Leishmania donovani by Enhancing Arginase-Mediated Polyamine Synthesis

• Published in: Frontiers in immunology 2017-07, Vol.8, p.839
• Main Authors: Mandal, Abhishek, Das, Sushmita, Kumar, Ajay, Roy, Saptarshi, Verma, Sudha, Ghosh, Ayan Kumar, Singh, Ruby, Abhishek, Kumar, Saini, Savita, Sardar, Abul Hasan, Purkait, Bidyut, Kumar, Ashish, Mandal, Chitra, Das, Pradeep
• Format: Article
• Language: English
• Subjects: arginase; CAT-2; Immunology; l-arginine; Leishmania; macrophage; nitric oxide
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2017.00839

The survival of intracellular protozoan parasite, , the causative agent of Indian visceral leishmaniasis (VL), depends on the activation status of macrophages. l-Arginine, a semi-essential amino acid plays a crucial regulatory role for activation of macrophages. However, the role of l-arginine transport in VL still remains elusive. In this study, we demonstrated that intra-macrophage survival of depends on the availability of extracellular l-arginine. Infection of THP-1-derived macrophage/human monocyte-derived macrophage (hMDM) with , resulted in upregulation of l-arginine transport. While investigating the involvement of the transporters, we observed that survival was greatly impaired when the transporters were blocked either using inhibitor or siRNA-mediated downregulation. CAT-2 was found to be the main isoform associated with l-arginine transport in -infected macrophages. l-arginine availability and its transport regulated the host arginase in infection. Arginase and inducible nitric oxide synthase (iNOS) expression were reciprocally regulated when assayed using specific inhibitors and siRNA-mediated downregulation. Interestingly, induction of iNOS expression and nitric oxide production were observed in case of inhibition of arginase in infected macrophages. Furthermore, inhibition of l-arginine transport as well as arginase resulted in decreased polyamine production, limiting parasite survival inside macrophages. l-arginine availability and transport regulated Th1/Th2 cytokine levels in case of infection. Upregulation of l-arginine transport, induction of host arginase, and enhanced polyamine production were correlated with increased level of IL-10 and decreased level of IL-12 and TNF-α in -infected macrophages. Our findings provide clear evidence for targeting the metabolism of l-arginine and l-arginine-metabolizing enzymes as an important therapeutic and prophylactic strategy to treat VL.