IFN-γ Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response.
The priming of macrophages with IFN-γ prior to TLR stimulation results in enhanced and prolonged inflammatory cytokine production. In this study, we demonstrate that, following TLR stimulation, macrophages upregulate the adenosine 2b receptor (A2bR) to enhance their sensitivity to immunosuppressive extracellular adenosine. This upregulation of A2bR leads to the induction of macrophages with an immunoregulatory phenotype and the downregulation of inflammation. IFN-γ priming of macrophages selectively prevents the induction of the A2bR in macrophages to mitigate sensitivity to adenosine and to prevent this regulatory transition. IFN-γ-mediated A2bR blockade leads to a prolonged production of TNF-α and IL-12 in response to TLR ligation. The pharmacologic inhibition or the genetic deletion of the A2bR results in a hyperinflammatory response to TLR ligation, similar to IFN-γ treatment of macrophages. Conversely, the overexpression of A2bR on macrophages blunts the IFN-γ effects and promotes the development of immunoregulatory macrophages. Thus, we propose a novel mechanism whereby IFN-γ contributes to host defense by desensitizing macrophages to the immunoregulatory effects of adenosine. This mechanism overcomes the transient nature of TLR activation, and prolongs the antimicrobial state of the classically activated macrophage. This study may offer promising new targets to improve the clinical outcome of inflammatory diseases in which macrophage activation is dysregulated.
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742; Maryland Pathogen Research Institute, College Park, MD 20742; and.
Heather B
HB
Cohen
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742; Maryland Pathogen Research Institute, College Park, MD 20742; and.
Amanda
A
Ward
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742; Maryland Pathogen Research Institute, College Park, MD 20742; and.
Kajal
K
Hamidzadeh
School of Medicine, Boston University, Boston, MA 02118.
Katya
K
Ravid
Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742; Maryland Pathogen Research Institute, College Park, MD 20742; and dmosser@umd.edu.
David M
DM
Mosser
D000818:Animals; D005260:Female; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D043704:Receptor, Adenosine A2B / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D043704:Receptor, Adenosine A2B; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma