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Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness

The type II IFN (IFNγ) enhances antimicrobial activity yet also drives expression of genes that amplify inflammatory responses. Hence, excessive IFNγ stimulation can be pathogenic. Here, we describe a previously unappreciated mechanism whereby IFNγ itself dampens myeloid cell activation. Staining of...

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Detalles Bibliográficos
Autores principales: Crisler, William J, Eshleman, Emily M, Lenz, Laurel L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Life Science Alliance LLC 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778285/
https://www.ncbi.nlm.nih.gov/pubmed/31585982
http://dx.doi.org/10.26508/lsa.201900447
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author Crisler, William J
Eshleman, Emily M
Lenz, Laurel L
author_facet Crisler, William J
Eshleman, Emily M
Lenz, Laurel L
author_sort Crisler, William J
collection PubMed
description The type II IFN (IFNγ) enhances antimicrobial activity yet also drives expression of genes that amplify inflammatory responses. Hence, excessive IFNγ stimulation can be pathogenic. Here, we describe a previously unappreciated mechanism whereby IFNγ itself dampens myeloid cell activation. Staining of monocytes from Listeria monocytogenes–infected mice provided evidence of type I IFN–independent reductions in IFNGR1. IFNγ was subsequently found to reduce surface IFNGR1 on cultured murine myeloid cells and human CD14(+) peripheral blood mononuclear cells. IFNγ-driven reductions in IFNGR1 were not explained by ligand-induced receptor internalization. Rather, IFNγ reduced macrophage Ifngr1 transcription by altering chromatin structure at putative Ifngr1 enhancer sites. This is a distinct mechanism from that used by type I IFNs. Ligand-induced reductions in IFNGR1 altered myeloid cell sensitivity to IFNγ, blunting activation of STAT1 and 3. Our data, thus, reveal a mechanism by which IFNGR1 abundance and myeloid cell sensitivity to IFNγ can be modulated in the absence of type I IFNs. Multiple mechanisms, thus, exist to calibrate macrophage IFNGR1 abundance, likely permitting the fine tuning of macrophage activation and inflammation.
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spelling pubmed-67782852019-10-07 Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness Crisler, William J Eshleman, Emily M Lenz, Laurel L Life Sci Alliance Research Articles The type II IFN (IFNγ) enhances antimicrobial activity yet also drives expression of genes that amplify inflammatory responses. Hence, excessive IFNγ stimulation can be pathogenic. Here, we describe a previously unappreciated mechanism whereby IFNγ itself dampens myeloid cell activation. Staining of monocytes from Listeria monocytogenes–infected mice provided evidence of type I IFN–independent reductions in IFNGR1. IFNγ was subsequently found to reduce surface IFNGR1 on cultured murine myeloid cells and human CD14(+) peripheral blood mononuclear cells. IFNγ-driven reductions in IFNGR1 were not explained by ligand-induced receptor internalization. Rather, IFNγ reduced macrophage Ifngr1 transcription by altering chromatin structure at putative Ifngr1 enhancer sites. This is a distinct mechanism from that used by type I IFNs. Ligand-induced reductions in IFNGR1 altered myeloid cell sensitivity to IFNγ, blunting activation of STAT1 and 3. Our data, thus, reveal a mechanism by which IFNGR1 abundance and myeloid cell sensitivity to IFNγ can be modulated in the absence of type I IFNs. Multiple mechanisms, thus, exist to calibrate macrophage IFNGR1 abundance, likely permitting the fine tuning of macrophage activation and inflammation. Life Science Alliance LLC 2019-10-04 /pmc/articles/PMC6778285/ /pubmed/31585982 http://dx.doi.org/10.26508/lsa.201900447 Text en © 2019 Crisler et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Crisler, William J
Eshleman, Emily M
Lenz, Laurel L
Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness
title Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness
title_full Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness
title_fullStr Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness
title_full_unstemmed Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness
title_short Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness
title_sort ligand-induced ifngr1 down-regulation calibrates myeloid cell ifnγ responsiveness
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778285/
https://www.ncbi.nlm.nih.gov/pubmed/31585982
http://dx.doi.org/10.26508/lsa.201900447
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