TY - JOUR T1 - Ligand-induced IFNGR1 down-regulation calibrates myeloid cell IFNγ responsiveness JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201900447 VL - 2 IS - 5 SP - e201900447 AU - William J Crisler AU - Emily M Eshleman AU - Laurel L Lenz Y1 - 2019/10/01 UR - https://www.life-science-alliance.org/content/2/5/e201900447.abstract N2 - 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. ER -