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Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFN? responsiveness.

ABSTRACT: The type II IFN (IFN?) enhances antimicrobial activity yet also drives expression of genes that amplify inflammatory responses. Hence, excessive IFN? stimulation can be pathogenic. Here, we describe a previously unappreciated mechanism whereby IFN? itself dampens myeloid cell activation. Staining of monocytes from Listeria monocytogenes-infected mice provided evidence of type I IFN-independent reductions in IFNGR1. IFN? was subsequently found to reduce surface IFNGR1 on cultured murine myeloid cells and human CD14+ peripheral blood mononuclear cells. IFN?-driven reductions in IFNGR1 were not explained by ligand-induced receptor internalization. Rather, IFN? 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 IFN?, blunting activation of STAT1 and 3. Our data, thus, reveal a mechanism by which IFNGR1 abundance and myeloid cell sensitivity to IFN? 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.


PROVIDER: S-EPMC6778285 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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