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

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.

Quantitative Proteomics of Polarised Macrophages Derived from Induced Pluripotent Stem Cells

“…However, polarisation of iPSDM with IFNγ and LPS downregulated the expression of these receptors ( Figure 3 A,D). As shown previously [ 38 ], stimulation with IFNγ significantly reduced the expression of its counter receptor IFNGR1 and this could be a feedback mechanism to dampen the inflammatory response in M Φ .…”

Single cell RNA sequencing identifies an early monocyte gene signature in acute respiratory distress syndrome

“…While all monocyte clusters were found to express IFNGR1 at similar levels, expression of IFNAR1 was low (Supplemental Figure 4). Low expression of IFNAR1 may be due to ligand-mediated downregulation of the receptor, as was recently reported for IFNGR1 in human monocytes (24). Expression of GBP1 -which encodes a member of the family of guanylate-binding proteins (GBPs), with functions in host defense (33,34) was expressed at a higher level in CD16 + monocytes, and the expression of multiple ISGs was also higher in the cells of ARDS patients (Figure 4).…”

“…Expression of the IFN-inducible genes, IFI44L and IFITM3, was upregulated in NK cells of ARDS patients, while, interestingly, expression of IFNGR1 was undetectable (Figure 2C). IFNGR1 is ubiquitously expressed by all cell types, and its downregulation may prevent proinflammatory responses to IFN-γ, as recently observed in human monocytes (24). Pathway enrichment analysis using the 102 suppressed genes (Bonferroni-corrected P < 0.01, logFC < -0.1) revealed pathways inhibited in ARDS patients.…”

Interferons alpha and gamma, pidotimod, and tilorone in the treatment of acute respiratory infections in patients with allergic rhinitis: a prospective, cohort clinical and immunological study

“…Взаимодействие ИФН-γ с рецептором в конечном итоге также приводит к интернализации и внутриклеточной деградации комплекса лиганд-рецептор [39]. ИФН-γ снижает в клетках-мишенях экспрессию своего рецептора и по независимым от эндоцитоза механизмам [40]. ИФН I типа также способны подавлять экспрессию рецепторов ИФН-γ как в результате блокировки транскрипции гена α-цепи этого рецептора [41], так и вторично за счет стимуляции выработки ИФН-γ [17], ведущей к упомянутым выше лиганд-индуцированным механизмам снижения чувствительности к ИФН-γ.…”