IRF3 inhibits IFN-γ-mediated restriction of intracellular pathogens in macrophages independently of IFNAR.
Macrophages use an array of innate immune sensors to detect intracellular pathogens and to tailor effective antimicrobial responses. In addition, extrinsic activation with the cytokine IFN-γ is often required as well to tip the scales of the host-pathogen balance toward pathogen restriction. However, little is known about how host-pathogen sensing impacts the antimicrobial IFN-γ-activated state. It was observed that in the absence of IRF3, a key downstream component of pathogen sensing pathways, IFN-γ-primed macrophages more efficiently restricted the intracellular bacterium Legionella pneumophila and the intracellular protozoan parasite Trypanosoma cruzi. This effect did not require IFNAR, the receptor for Type I IFNs known to be induced by IRF3, nor the sensing adaptors MyD88/TRIF, MAVS, or STING. This effect also did not involve differential activation of STAT1, the major signaling protein downstream of both Type 1 and Type 2 IFN receptors. IRF3-deficient macrophages displayed a significantly altered IFN-γ-induced gene expression program, with up-regulation of microbial restriction factors such as Nos2. Finally, we found that IFN-γ-primed but not unprimed macrophages largely excluded the activated form of IRF3 from the nucleus following bacterial infection. These data are consistent with a relationship of mutual inhibition between IRF3 and IFN-γ-activated programs, possibly as a component of a partially reversible mechanism for modulating the activity of potent innate immune effectors (such as Nos2) in the context of intracellular infection.
Duke Scholars
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- Trypanosoma cruzi
- Nitric Oxide Synthase Type II
- Macrophages
- Legionella pneumophila
- Interferon-gamma
- Interferon Regulatory Factor-3
- Immunology
- Adaptor Proteins, Signal Transducing
- 3204 Immunology
- 1107 Immunology
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Trypanosoma cruzi
- Nitric Oxide Synthase Type II
- Macrophages
- Legionella pneumophila
- Interferon-gamma
- Interferon Regulatory Factor-3
- Immunology
- Adaptor Proteins, Signal Transducing
- 3204 Immunology
- 1107 Immunology