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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.

SUBMITTER: Crisler WJ

PROVIDER: S-EPMC6778285 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Crisler William J WJ Eshleman Emily M EM Lenz Laurel L LL

Life science alliance 20191004 5

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 <i>Listeria monocytogenes</i>-infected mice provided evidence of type I IFN-independent reductions in IFNGR1. IFNγ was subsequently found to reduce surface IFNGR1 on cultured murine my ...[more]

PMID: 31585982

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Project description:Background and purposeMany GPCRs, including the CB(1) cannabinoid receptor, are down-regulated following prolonged agonist exposure by interacting with the GPCR-associated sorting protein-1 (GASP-1). The CB(1) receptor antagonist rimonabant has also recently been described to be an agonist at GPR55, a cannabinoid-related receptor. Here we investigated the post-endocytic properties of GPR55 after agonist exposure and tested whether GASP-1 is involved in this process.Experimental approachWe evaluated the direct protein-protein interaction of GPR55 with GASP-1 using (i) GST-binding assays and (ii) co-immunoprecipitation assays in GPR55-HEK293 cells with endogenous GASP-1 expression. We further tested the internalization, recycling and degradation of GPR55 using confocal fluorescence microscopy and biotinylation assays in the presence and absence of GASP-1 (lentiviral small hairpin RNA knockdown of GASP-1) under prolonged agonist [rimonabant (RIM), lysophosphatidylinositol (LPI)] stimulation.Key resultsWe showed that the prolonged activation of GPR55 with rimonabant or LPI down-regulates GPR55 via GASP-1. GASP-1 binds to GPR55 in vitro, and this interaction was required for targeting GPR55 for degradation. Disrupting the GPR55-GASP-1 interaction prevented post-endocytic receptor degradation, and thereby allowed receptor recycling.Conclusion and implicationsThese data implicate GASP-1 as an important regulator of ligand-mediated down-regulation of GPR55. By identifying GASP-1 as a key regulator of the trafficking and, by extension, functional expression of GPR55, we may be one step closer to gaining a better understanding of this receptor in response to cannabinoid drugs.Linked articlesThis article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.

Dataset Information

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

Publications

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

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