The Francis Crick Institute
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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-γ signaling

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journal contribution
posted on 2020-09-07, 11:21 authored by Lúcia Moreira-Teixeira, Jeremy Sousa, Finlay W McNab, Egídio Torrado, Filipa Cardoso, Henrique Machado, Flávia Castro, Vânia Cardoso, Joana Gaifem, Xuemei Wu, Rui Appelberg, António Gil Castro, Anne O'Garra, Margarida Saraiva
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.