title: Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas.
abstract: Lung granulomas develop upon Mycobacterium tuberculosis (Mtb) infection as a hallmark of human tuberculosis (TB). They are structured aggregates consisting mainly of Mtb-infected and -uninfected macrophages and Mtb-specific T cells. The production of NO by granuloma macrophages expressing nitric oxide synthase-2 (NOS2) via l-arginine and oxygen is a key protective mechanism against mycobacteria. Despite this protection, TB granulomas are often hypoxic, and bacterial killing via NOS2 in these conditions is likely suboptimal. Arginase-1 (Arg1) also metabolizes l-arginine but does not require oxygen as a substrate and has been shown to regulate NOS2 via substrate competition. However, in other infectious diseases in which granulomas occur, such as leishmaniasis and schistosomiasis, Arg1 plays additional roles such as T-cell regulation and tissue repair that are independent of NOS2 suppression. To address whether Arg1 could perform similar functions in hypoxic regions of TB granulomas, we used a TB murine granuloma model in which NOS2 is absent. Abrogation of Arg1 expression in macrophages in this setting resulted in exacerbated lung granuloma pathology and bacterial burden. Arg1 expression in hypoxic granuloma regions correlated with decreased T-cell proliferation, suggesting that Arg1 regulation of T-cell immunity is involved in disease control. Our data argue that Arg1 plays a central role in the control of TB when NOS2 is rendered ineffective by hypoxia.
authors.affiliation: Department of Immunology and.
authors.forename: María A
authors.initials: MA
authors.lastname: Duque-Correa
authors.affiliation: Department of Immunopathology, Charité - University Medicine Berlin, 12200 Berlin, Germany;
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.affiliation: Department of Microbiology, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112;
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
authors.affiliation: Department of Immunology and.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Zedler
authors.affiliation: Department of Immunology and.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schommer-Leitner
authors.affiliation: Department of Immunology and.
authors.forename: Martin
authors.initials: M
authors.lastname: Rao
authors.affiliation: Department of Immunology and.
authors.forename: January
authors.initials: J
authors.lastname: Weiner
authors.affiliation: Central Support Unit Biochemistry, Max Planck Institute for Infection Biology, 10117 Berlin, Germany;
authors.forename: Robert
authors.initials: R
authors.lastname: Hurwitz
authors.affiliation: Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Qualls
authors.affiliation: Immunology and Thoracic Surgery, Central Tuberculosis Research Institute, Moscow 107564, Russian Federation.
authors.forename: George A
authors.initials: GA
authors.lastname: Kosmiadi
authors.affiliation: Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Murray
authors.affiliation: Department of Immunology and kaufmann@mpiib-berlin.mpg.de.
authors.forename: Stefan H E
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Department of Immunology and.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Reece
mesh_terms: D000818:Animals; D001119:Arginase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001120:Arginine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D006099:Granuloma / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis; D009569:Nitric Oxide / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014397:Tuberculosis, Pulmonary / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D009569:Nitric Oxide; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase