PMID- 34054815 OWN - NLM STAT- MEDLINE DCOM- 20210927 LR - 20211106 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - Promotion of Anti-Tuberculosis Macrophage Activity by L-Arginine in the Absence of Nitric Oxide. PG - 653571 LID - 10.3389/fimmu.2021.653571 [doi] LID - 653571 AB - Macrophages are indispensable immune cells tasked at eliminating intracellular pathogens. Mycobacterium tuberculosis (Mtb), one of the most virulent intracellular bacterial pathogens known to man, infects and resides within macrophages. While macrophages can be provoked by extracellular stimuli to inhibit and kill Mtb bacilli, these host defense mechanisms can be blocked by limiting nutritional metabolites, such as amino acids. The amino acid L-arginine has been well described to enhance immune function, especially in the context of driving macrophage nitric oxide (NO) production in mice. In this study, we aimed to establish the necessity of L-arginine on anti-Mtb macrophage function independent of NO. Utilizing an in vitro system, we identified that macrophages relied on NO for only half of their L-arginine-mediated host defenses and this L-arginine-mediated defense in the absence of NO was associated with enhanced macrophage numbers and viability. Additionally, we observed macrophage glycolysis to be driven by both L-arginine and mechanistic target of rapamycin (mTOR), and inhibition of glycolysis or mTOR reduced macrophage control of Mtb as well as macrophage number and viability in the presence of L-arginine. Our data underscore L-arginine as an essential nutrient for macrophage function, not only by fueling anti-mycobacterial NO production, but also as a central regulator of macrophage metabolism and additional host defense mechanisms. CI - Copyright (c) 2021 McKell, Crowther, Schmidt, Robillard, Cantrell, Lehn, Janssen and Qualls. FAU - McKell, Melanie C AU - McKell MC AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. AD - Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States. FAU - Crowther, Rebecca R AU - Crowther RR AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. AD - Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States. FAU - Schmidt, Stephanie M AU - Schmidt SM AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. FAU - Robillard, Michelle C AU - Robillard MC AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. AD - Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States. FAU - Cantrell, Rachel AU - Cantrell R AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Immunology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. FAU - Lehn, Maria A AU - Lehn MA AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. FAU - Janssen, Edith M AU - Janssen EM AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. FAU - Qualls, Joseph E AU - Qualls JE AD - Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States. AD - Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. LA - eng GR - R01 AI116668/AI/NIAID NIH HHS/United States GR - T32 AI118697/AI/NIAID NIH HHS/United States GR - T32 GM063483/GM/NIGMS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210514 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 31C4KY9ESH (Nitric Oxide) RN - 94ZLA3W45F (Arginine) RN - EC 4.3.2.1 (Argininosuccinate Lyase) RN - EC 6.3.4.5 (Argininosuccinate Synthase) SB - IM MH - Animals MH - Arginine/administration & dosage/*metabolism MH - Argininosuccinate Lyase/genetics/metabolism MH - Argininosuccinate Synthase/genetics/metabolism MH - Cell Survival MH - *Dietary Supplements MH - Disease Models, Animal MH - Humans MH - Macrophage Activation MH - Macrophages/*immunology/metabolism MH - Mice MH - Mice, Knockout MH - Mycobacterium tuberculosis/*immunology MH - Nitric Oxide/metabolism MH - Primary Cell Culture MH - RAW 264.7 Cells MH - Tuberculosis/*diet therapy/immunology/microbiology PMC - PMC8160513 OTO - NOTNLM OT - arginine OT - citrulline OT - glycolysis OT - macrophage OT - tuberculosis COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/06/01 06:00 MHDA- 2021/09/28 06:00 PMCR- 2021/01/01 CRDT- 2021/05/31 06:08 PHST- 2021/01/14 00:00 [received] PHST- 2021/04/26 00:00 [accepted] PHST- 2021/05/31 06:08 [entrez] PHST- 2021/06/01 06:00 [pubmed] PHST- 2021/09/28 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.653571 [doi] PST - epublish SO - Front Immunol. 2021 May 14;12:653571. doi: 10.3389/fimmu.2021.653571. eCollection 2021.