Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection

PLoS Pathogens

Staci J. Kearney¹  Laurel L. Lenz¹  Christine Delgado²  Emily M. Eshleman²  Rachel S. Friedman² 

[1] Department of Biomedical Sciences, National Jewish Health, Denver, CO United States of America;Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO United States of America

关键词: Macrophages;    Listeria monocytogenes;    Monocytes;    Inflammation;    Bone marrow cells;    Spleen;    Interferons;    Mouse models;   

DOI  :  10.1371/journal.ppat.1006388

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY