The Crucial Role of L-Arginine Substrate Competition in Dendritic Cell Function: Toggling between Nitric Oxide (NO)-mediated host cellular respiration inhibition and antimicrobial activity 9005

Abstract Description Two major L-arginine metabolizing enzymes, Nitric oxide synthase (iNOS) and Arginase (ARG), pivot a central regulatory axis in the immune system. The products of these enzymes, NO and L-ornithine, respectively, help set different inflammatory microenvironments. Though expressions of these enzymes were reported in DCs, there is a gap in knowledge regarding the substrate competition and its significance/impact on DC, as they function as modulators of infection and key linkers of innate and adaptive immunity. To investigate the hypothesis that DCs regulate NO production via L-arginine substrate competition by ARG, Bone Marrow-derived DCs (BMDCs) were examined as our study model with/without pharmacological inhibitors of iNOS/ARG. The results revealed that DCs co-express ARG1(cytosolic) and iNOS in a LPS dose-dependent manner, whereas ARG2 (mitochondrial) was minimally affected. ARG inhibition led to increased iNOS with enhanced NO production, consequently stalling cellular respiration and shortening DC lifespan, compared to control DCs without ARG inhibition. Contrastingly, this enhanced NO bolsters the host-protective role by attenuating the replication of Listeria monocytogenes. These findings suggest a cellular NO-respiration threshold/concentration and support our hypothesis that DC cellular function is partially regulated by arginine substrate competition, with important implications for the field of immunology and inflammation, particularly in disease settings. Funding Sources Supported by NIH NIAID R01 AI158710-01 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)