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Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection.


ABSTRACT: Interferons (IFNs) target macrophages to regulate inflammation and resistance to microbial infections. The type II IFN (IFN?) acts on a cell surface receptor (IFNGR) to promote gene expression that enhance macrophage inflammatory and anti-microbial activity. Type I IFNs can dampen macrophage responsiveness to IFN? and are associated with increased susceptibility to numerous bacterial infections. The precise mechanisms responsible for these effects remain unclear. Type I IFNs silence macrophage ifngr1 transcription and thus reduce cell surface expression of IFNGR1. To test how these events might impact macrophage activation and host resistance during bacterial infection, we developed transgenic mice that express a functional FLAG-tagged IFNGR1 (fGR1) driven by a macrophage-specific promoter. Macrophages from fGR1 mice expressed physiologic levels of cell surface IFNGR1 at steady state and responded equivalently to WT C57Bl/6 macrophages when treated with IFN? alone. However, fGR1 macrophages retained cell surface IFNGR1 and showed enhanced responsiveness to IFN? in the presence of type I IFNs. When fGR1 mice were infected with the bacterium Listeria monocytogenes their resistance was significantly increased, despite normal type I and II IFN production. Enhanced resistance was dependent on IFN? and associated with increased macrophage activation and antimicrobial function. These results argue that down regulation of myeloid cell IFNGR1 is an important mechanism by which type I IFNs suppress inflammatory and anti-bacterial functions of macrophages.

SUBMITTER: Eshleman EM 

PROVIDER: S-EPMC5457163 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

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