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Type I IFN inhibits alternative macrophage activation during Mycobacterium tuberculosis infection and leads to enhanced protection in the absence of IFN-gamma signaling

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Title: Type I IFN inhibits alternative macrophage activation during Mycobacterium tuberculosis infection and leads to enhanced protection in the absence of IFN-gamma signaling
Authors: Moreira-Teixeira, L
Sousa, J
McNab, FW
Torrado, E
Cardoso, F
Machado, H
Castro, F
Cardoso, V
Gaifem, J
Wu, X
Appelberg, R
Castro, AG
O'Garra, A
Saraiva, M
Item Type: Journal Article
Abstract: Tuberculosis causes ∼1.5 million deaths every year, thus remaining a leading cause of death from infectious diseases in the world. A growing body of evidence demonstrates that type I IFN plays a detrimental role in tuberculosis pathogenesis, likely by interfering with IFN-γ–dependent immunity. In this article, we reveal a novel mechanism by which type I IFN may confer protection against Mycobacterium tuberculosis infection in the absence of IFN-γ signaling. We show that production of type I IFN by M. tuberculosis–infected macrophages induced NO synthase 2 and inhibited arginase 1 gene expression. In vivo, absence of both type I and type II IFN receptors led to strikingly increased levels of arginase 1 gene expression and protein activity in infected lungs, characteristic of alternatively activated macrophages. This correlated with increased lung bacterial burden and pathology and decreased survival compared with mice deficient in either receptor. Increased expression of other genes associated with alternatively activated macrophages, as well as increased expression of Th2-associated cytokines and decreased TNF expression, were also observed. Thus, in the absence of IFN-γ signaling, type I IFN suppressed the switching of macrophages from a more protective classically activated phenotype to a more permissive alternatively activated phenotype. Together, our data support a model in which suppression of alternative macrophage activation by type I IFN during M. tuberculosis infection, in the absence of IFN-γ signaling, contributes to host protection.
Issue Date: 2-Dec-2016
Date of Acceptance: 17-Oct-2016
URI: http://hdl.handle.net/10044/1/44585
DOI: http://dx.doi.org/10.4049/jimmunol.1600584
ISSN: 1550-6606
Publisher: American Association of Immunologists
Start Page: 4714
End Page: 4726
Journal / Book Title: Journal of Immunology
Volume: 197
Issue: 12
Copyright Statement: © 2016 The Authors. This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license (https://creativecommons.org/licenses/by/3.0/).
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
NITRIC-OXIDE SYNTHASE
L-ARGININE METABOLISM
INTERFERON-GAMMA
IMMUNE-RESPONSES
PULMONARY TUBERCULOSIS
IL-1-BETA PRODUCTION
EXPRESSION
MICE
GENE
ALPHA
1107 Immunology
Publication Status: Published
Appears in Collections:National Heart and Lung Institute