期刊
JOURNAL OF IMMUNOLOGY
卷 197, 期 12, 页码 4714-4726出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1600584
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资金
- Fundacao para a Ciencia e Tecnologia, Portugal
- Programa Operacional Regional do Norte [ON. 2 - O Novo Norte]
- Quadro de Referencia Estrategico Nacional through the Fundo Europeu de Desenvolvimento Regional [PTDC/SAU-MII/101977/2008, PTDC/BIABCM/102776/2008]
- Francis Crick Institute
- Cancer Research U.K. [FC001126]
- U.K. Medical Research Council [FC001126, MR/U117565642/1]
- Wellcome Trust [FC001126]
- European Research Council [294682-TB-PATH]
- European Society of Clinical Microbiology and Infectious Diseases
- Fundacao para a Ciencia e Tecnologia [SFRH/BPD/77399/2011]
- Fundo Europeu de Desenvolvimento Regional (FEDER) funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal
- Portuguese funds through Fundacao para a Ciencia e Tecnologia, Portugal [POCI01-0145-FEDER-007274]
- MRC [MC_U117565642] Funding Source: UKRI
- Cancer Research UK
- The Francis Crick Institute [10126] Funding Source: researchfish
- Medical Research Council [MC_U117565642, 1365570, 1105853] Funding Source: researchfish
- The Francis Crick Institute [10127] Funding Source: researchfish
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-MII/101977/2008, PTDC/BIA-BCM/102776/2008] Funding Source: FCT
Tuberculosis causes similar to 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-gamma-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-gamma 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-gamma 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-gamma signaling, contributes to host protection.
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