The ability of type I interferons (IFNs) to increase susceptibility to certain bacterial infections correlates with down regulation of myeloid cell surface IFNGR, the receptor for the type II IFN (IFNγ), and reduced myeloid cell responsiveness to IFNγ. Here, we show that the rapid reductions in mouse and human myeloid cell surface IFNGR1 expression that occur in response to type I IFN treatment reflect a rapid silencing of new ifngr1 transcription by repressive transcriptional regulators. Treatment of macrophages with IFNβ reduced cellular abundance of ifngr1 transcripts as rapidly and effectively as actinomycin D treatment. IFNβ treatment also significantly reduced the amounts of activated RNA polymerase II (pol II) and acetylated histones H3 and H4 at the ifngr1 promoter, and the activity of an ifngr1-luc reporter construct in macrophages. The suppression of ifngr1-luc activity required an intact early growth response factor (Egr)-binding site in the proximal ifngr1 promoter. Three Egr proteins and two Egr/NGFI-A binding (Nab) proteins were found to be expressed in bone macrophages, but only Egr3 and Nab1 were recruited to the ifngr1 promoter upon IFNβ stimulation. Knockdown of Nab1 in a macrophage cell line prevented down regulation of IFNGR1 and prevented the loss of acetylated histones from the ifngr1 promoter. These data suggest that type I IFN stimulation induces a rapid recruitment of a repressive Egr3/Nab1 complex that silences transcription from the ifngr1 promoter. This mechanism of gene silencing may contribute to the anti-inflammatory effects of type I IFNs.
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.
The type I and II interferons (IFNs) play important roles in regulating immune responses during viral and bacterial infections and in the context of autoimmune and neoplastic diseases. These two IFN types bind to distinct cell surface receptors that are expressed by nearly all cells to trigger signal transduction events and elicit diverse cellular responses. In some cases, type I and II IFNs trigger similar cellular responses while in other cases the IFNs have unique or antagonistic effects on host cells. Negative regulators of IFN signaling also modulate cellular responses to the IFNs and play important roles in maintaining immunological homeostasis. In this review article, we provide an overview of how IFNs stimulate cellular responses. We discuss the disparate effects of type I and II IFNs on host resistance to certain intracellular bacterial infections and provide an overview of models that have been proposed to account for these disparate effects. Mechanisms of antagonistic cross talk between type I and II IFNs are also introduced.
Sampling of mucosal antigens regulates immune responses but may also promote dissemination of mucosal pathogens. Lung dendritic cells (LDC) capture antigens and traffic them to lung-draining lymph nodes (LDLNs) dependent on the chemokine receptor CCR7. LDCs also capture lung pathogens such as Bacillus anthracis (BA). However, we show here that the initial traffic of BA spores from lungs to LDLN is largely independent of LDCs and CCR7, occurring instead in association with B cells. BA spores rapidly bound B cells in lungs and cultured mouse and human B cells. Binding was independent of the B cell receptor (BCR). B cells instilled in the lungs trafficked to LDLN and BA spore traffic to LDLN was impaired by B cell deficiency. Depletion of B cells also delayed death of mice receiving a lethal BA infection. These results suggest that mucosal B cells traffic BA, and possibly other antigens, from lungs to LDLN.
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