Abstract
Interferons (IFNs) target macrophages to regulate inflammation and resistance to microbial infections. The type II IFN (IFNγ) 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 IFNγ 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 IFNγ alone. However, fGR1 macrophages retained cell surface IFNGR1 and showed enhanced responsiveness to IFNγ 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 IFNγ 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.
Highlights
Interferons (IFN) are critical mediators of host immunity
To distinguish between the above models and test the importance of type I IFN driven down regulation of IFNGR1, we developed a transgenic mouse line in which a functional FLAG-tagged IFNGR1 is selectively expressed in macrophages using the well-characterized c-fms promoter [29,30]
Commercial and custom antibodies directed at the FLAG epitope stained macrophages and monocytes but not other cell populations from the FLAG-tagged IFNGR1 (fGR1) mice
Summary
Interferons (IFN) are critical mediators of host immunity. These cytokines are classified into two major groups: type I and type II. Type I IFNs are a family of homologous proteins including various IFNα subtypes and a single IFNβ [1,2] They are synthesized and secreted in response to ligation of transmembrane or cytosolic pattern recognition receptors (PRR) by a variety of microbial products [3]. Ligation of IFNAR activates TYK2 and JAK1 kinases to phosphorylate signal transducers and activator of transcription (STAT) proteins 1 and 2 [2,4] These activated STATs associate with IRF9 to induce transcription of numerous IFN-stimulated genes (ISGs) whose products restrict viral replication [1]. Type I IFNs impact cell survival and can have anti-inflammatory effects [3] They are used therapeutically in treatment of chronic viral infections, cancers, and the autoimmune disease multiple sclerosis
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