Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness. Life Sci Alliance 2019 Oct;2(5)
Date
10/06/2019Pubmed ID
31585982Pubmed Central ID
PMC6778285DOI
10.26508/lsa.201900447Scopus ID
2-s2.0-85072940574 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
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.
Author List
Crisler WJ, Eshleman EM, Lenz LLAuthor
Emily M. Eshleman PhD Assistant Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCD4 Antigens
Cells, Cultured
Chromatin
Enhancer Elements, Genetic
Female
Humans
Interferon-gamma
Leukocytes, Mononuclear
Ligands
Listeria monocytogenes
Male
Mice
Monocytes
Myeloid Cells
Receptors, Interferon
Transcription, Genetic
