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Proc Natl Acad Sci U S A. 2014 Sep 23;111(38):E4024-32. doi: 10.1073/pnas.1408839111. Epub 2014 Sep 8.

Macrophage arginase-1 controls bacterial growth and pathology in hypoxic tuberculosis granulomas.

Author information

1
Department of Immunology and.
2
Department of Immunopathology, Charité - University Medicine Berlin, 12200 Berlin, Germany;
3
Department of Microbiology, Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112;
4
Central Support Unit Biochemistry, Max Planck Institute for Infection Biology, 10117 Berlin, Germany;
5
Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105; and.
6
Immunology and Thoracic Surgery, Central Tuberculosis Research Institute, Moscow 107564, Russian Federation.
7
Department of Immunology and kaufmann@mpiib-berlin.mpg.de.

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.

PMID:
25201986
PMCID:
PMC4183271
DOI:
10.1073/pnas.1408839111
[Indexed for MEDLINE]
Free PMC Article

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