title: Adenosine Modulates NR4A Orphan Nuclear Receptors To Attenuate Hyperinflammatory Responses in Monocytic Cells.
abstract: Adenosine receptor-mediated regulation of monocyte/macrophage inflammatory responses is critical in the maintenance of tissue homeostasis. In this study, we reveal that adenosine potently modulates the expression of NR4A1, 2, and 3 orphan nuclear receptors in myeloid cells, and this modulation is primarily through the adenosine A2a receptor subtype. We demonstrate that A2a receptor activation of NR4A1-3 receptor synthesis is further enhanced in TLR4-stimulated monocytes. After TLR4 stimulation, NR4A receptor-depleted monocyte/macrophage cells display significantly altered expression of cell-surface markers and produce increased inflammatory cytokine and chemokine secretion rendering the cells an enhanced proinflammatory phenotype. Exposure of TLR4 or TNF-α-stimulated monocytes to adenosine analogs directs changes in the expression of MIP-3α and IL-23p19, with NR4A2 depletion leading to significantly enhanced expression of these factors. Furthermore, we establish that nuclear levels of NF-κB/p65 are increased in TLR/adenosine-stimulated NR4A2-depleted cells. We show that, after TLR/adenosine receptor stimulation, NR4A2 depletion promotes significant binding of NF-κB/p65 to a κB consensus binding motif within the MIP-3α proximal promoter leading to increased protein secretion, confirming a pivotal role for NF-κB activity in controlling cellular responses and gene expression outcomes in response to these mediators. Thus, these data demonstrate that during an inflammatory response, adenosine modulation of NR4A receptor activity acts to limit NF-κB-mediated effects and that loss of NR4A2 expression leads to enhanced NF-κB activity and hyperinflammatory responses in myeloid cells.
authors.affiliation: UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland; and Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Crean
authors.affiliation: Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Cummins
authors.affiliation: UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland; and.
authors.forename: Bojlul
authors.initials: B
authors.lastname: Bahar
authors.affiliation: UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland; and.
authors.forename: Helen
authors.initials: H
authors.lastname: Mohan
authors.affiliation: UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland; and.
authors.forename: Jason P
authors.initials: JP
authors.lastname: McMorrow
authors.affiliation: UCD Veterinary Sciences Centre, University College Dublin, Belfield, Dublin 4, Ireland; and Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland evelyn.murphy@ucd.ie.
authors.forename: Evelyn P
authors.initials: EP
authors.lastname: Murphy
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D054418:Chemokine CCL20 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism; D057106:Nuclear Receptor Subfamily 4, Group A, Member 3 / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D043705:Receptor, Adenosine A2A / Q000378:metabolism
chemical_list: D054418:Chemokine CCL20; D004268:DNA-Binding Proteins; D053760:Interleukin-23 Subunit p19; D016328:NF-kappa B; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D057106:Nuclear Receptor Subfamily 4, Group A, Member 3; D057093:Orphan Nuclear Receptors; D043705:Receptor, Adenosine A2A; D000241:Adenosine