Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 38, Pages E4024-E4032Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1408839111
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Funding
- European Union's Seventh Framework Programme (EU FP7) Collaborative Project NEWTBVAC [HEALTH-F3-2009-241745]
- European Union's Seventh Framework Programme (EU FP7) Collaborative Project SysteMTb [HEALTH-F4-2010-241587]
- European Union's Seventh Framework Programme (EU FP7) Collaborative Project FP7 [280873 ADITEC.]
- CORE Grant [P30 CA21765]
- National Institutes of Health Grant [AI097485]
- Hartwell Foundation
- American Lebanese Syrian Associated Charities
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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.
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