Abstract
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.
Highlights
When microbes penetrate epithelial barriers, host pattern recognition receptors detect microbial or damage-associated host products (PAMPS or DAMPs)
Surface IFNGR1 geometric mean fluorescence intensity was reduced by nearly 50% on gated splenic monocytes (CD11b+Ly6C+Ly6G−) at 72 hpi from the infected control (PBS) mice versus naıve controls (Fig 1A)
These data are consistent with prior work using B6.Ifnar1−/− mice and indicate that blockade of type I IFNs suffices to prevent myeloid cell interferon gamma receptor (IFNGR) down-regulation seen at 72 hpi [22]
Summary
When microbes penetrate epithelial barriers, host pattern recognition receptors detect microbial or damage-associated host products (PAMPS or DAMPs). Pattern recognition receptor ligation signals the production of cytokines and other factors important for eliciting, shaping, and amplifying inflammatory responses [1, 2]. One family of cytokines critical for mediating inflammatory responses is the IFNs. Type II IFN (IFNγ) is a proinflammatory cytokine that boosts the antimicrobial functions of myeloid cells. The activated JAKs phosphorylate tyrosine residues in the IFNGR cytoplasmic domain to stimulate recruitment of signal transducer and activator of transcription (STAT) proteins, including STATs 1 and 3. Phosphorylation of STAT1 on Tyrosine 701 (pSTAT1Y701) induces the formation of canonical pSTAT1 homodimers, which translocate to the nucleus where they bind DNA to promote expression of IFNγ-activated genes (GAGs) [4]. Many GAGs encode proteins that boost inflammatory responses or increase myeloid cell antimicrobial activities. Defects in the IFNγ response increase susceptibility to diverse pathogens, including L. monocytogenes (Lm) and Mycobacterium tuberculosis (Mtb) [9, 10, 11, 12]
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