Cargando…
Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection
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 respons...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457163/ https://www.ncbi.nlm.nih.gov/pubmed/28542482 http://dx.doi.org/10.1371/journal.ppat.1006388 |
_version_ | 1783241485763739648 |
---|---|
author | Eshleman, Emily M. Delgado, Christine Kearney, Staci J. Friedman, Rachel S. Lenz, Laurel L. |
author_facet | Eshleman, Emily M. Delgado, Christine Kearney, Staci J. Friedman, Rachel S. Lenz, Laurel L. |
author_sort | Eshleman, Emily M. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5457163 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54571632017-06-06 Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection Eshleman, Emily M. Delgado, Christine Kearney, Staci J. Friedman, Rachel S. Lenz, Laurel L. PLoS Pathog Research Article 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. Public Library of Science 2017-05-22 /pmc/articles/PMC5457163/ /pubmed/28542482 http://dx.doi.org/10.1371/journal.ppat.1006388 Text en © 2017 Eshleman et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Eshleman, Emily M. Delgado, Christine Kearney, Staci J. Friedman, Rachel S. Lenz, Laurel L. Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection |
title | Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection |
title_full | Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection |
title_fullStr | Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection |
title_full_unstemmed | Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection |
title_short | Down regulation of macrophage IFNGR1 exacerbates systemic L. monocytogenes infection |
title_sort | down regulation of macrophage ifngr1 exacerbates systemic l. monocytogenes infection |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457163/ https://www.ncbi.nlm.nih.gov/pubmed/28542482 http://dx.doi.org/10.1371/journal.ppat.1006388 |
work_keys_str_mv | AT eshlemanemilym downregulationofmacrophageifngr1exacerbatessystemiclmonocytogenesinfection AT delgadochristine downregulationofmacrophageifngr1exacerbatessystemiclmonocytogenesinfection AT kearneystacij downregulationofmacrophageifngr1exacerbatessystemiclmonocytogenesinfection AT friedmanrachels downregulationofmacrophageifngr1exacerbatessystemiclmonocytogenesinfection AT lenzlaurell downregulationofmacrophageifngr1exacerbatessystemiclmonocytogenesinfection |