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Activation Response Upregulation to Sustain the Macrophage Prevents Adenosine Receptor (A2br) Γ IFN

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Activation Response Upregulation to Sustain the Macrophage Prevents Adenosine Receptor (A2br) Γ IFN IFN-γ Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response This information is current as Heather B. Cohen, Amanda Ward, Kajal Hamidzadeh, Katya of October 1, 2021. Ravid and David M. Mosser J Immunol 2015; 195:3828-3837; Prepublished online 9 September 2015; doi: 10.4049/jimmunol.1501139 http://www.jimmunol.org/content/195/8/3828 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2015/09/09/jimmunol.150113 Material 9.DCSupplemental http://www.jimmunol.org/ References This article cites 31 articles, 8 of which you can access for free at: http://www.jimmunol.org/content/195/8/3828.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IFN-g Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response Heather B. Cohen,*,†,1 Amanda Ward,*,† Kajal Hamidzadeh,*,† Katya Ravid,‡ and David M. Mosser*,† The priming of macrophages with IFN-g 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-g priming of macrophages selectively prevents the induction of the A2bR in macrophages to mitigate sensitivity to adenosine and to prevent this regulatory transition. IFN-g–mediated A2bR blockade leads to a prolonged production of TNF-a 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 Downloaded from ligation, similar to IFN-g treatment of macrophages. Conversely, the overexpression of A2bR on macrophages blunts the IFN-g effects and promotes the development of immunoregulatory macrophages. Thus, we propose a novel mechanism whereby IFN-g contributes to host defense by desensitizing macrophages to the immunoregulatory effects of adenosine. This mechanism over- comes 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. The Journal of Immunology, 2015, 195: 3828–3837. http://www.jimmunol.org/ xposure of macrophages to TLR ligands initiates the IFN-g represents a key component in chronic inflammatory production of inflammatory cytokines and mediators that environments (2). Activated NK cells, invariant NKT, and TH1 E can influence immune responses (1). The production of cells secrete IFN-g, which primes macrophages to increase their these cytokines and mediators must be tightly regulated because production of inflammatory cytokines and mediators (6). In this their overproduction can result in damage to surrounding tissue way, IFN-g plays vital roles in cell-mediated immunity and host (2). We recently described a negative feedback mechanism defense against intracellular pathogens (7). However, macro- whereby macrophages terminate the response to TLR stimuli to phages exhibiting an “IFN signature” are observed in rheumatoid prevent immunopathology (3). After TLR stimulation, macro- arthritis, multiple sclerosis, and many other autoimmune diseases, by guest on October 1, 2021 phages alter their metabolism and release low levels of ATP, indicating that IFN-g can have a pathogenic role during chronic which is rapidly converted into immunosuppressive adenosine via macrophage activation (8, 9). Although the ability of IFN-g to CD39-mediated hydrolysis. Adenosine promotes a transition to- enhance the inflammatory potential of TLR-activated macro- ward an immunoregulatory macrophage phenotype (4, 5). We also phages is a well-known phenomenon, how IFN-g affects the demonstrated that a deficiency of CD39 on macrophages resulted intrinsic regulation of macrophage activation remains to be in severe immunopathology in a mouse model of septic shock, determined. In this study, we investigated the effect of IFN-g on because of the inability of these cells to undergo this transition to TLR-activated macrophages, and we reveal that IFN-g sustains regulatory macrophages. Thus, the generation of adenosine by inflammatory macrophage activation by attenuating their sensi- macrophages is an important mechanism that prevents overactive tivity to extracellular adenosine. Extracellular adenosine can sig- inflammatory responses. nal through four different adenosine receptors, designated A1, A3, A2a, and A2b (10). The relative expression of these receptors varies with cell type, anatomic location, and activation state (11). We demonstrate that IFN-g treatment selectively blocks the in- *Department of Cell Biology and Molecular Genetics, University of Maryland, Col- duction of the adenosine 2b receptor (A2bR). We also show that lege Park, MD 20742; †Maryland Pathogen Research Institute, College Park, MD 20742; and ‡School of Medicine, Boston University, Boston, MA 02118 IFN-g inhibition of TLR-induced A2bR prevents completion of an important negative feedback loop, thus rendering macrophages 1Current address: ImmunoOncology, EMD Serono Research and Development Insti- tute, Billerica, MA. hyperinflammatory. Finally, we demonstrate that overexpression Received for publication May 18, 2015. Accepted for publication August 4, 2015. of A2bR on macrophages rescues their ability to respond to This work was supported in part by National Institutes of Health Grant R01 adenosine. Thus, we reveal the therapeutic potential of targeting GM102589. macrophage-specific A2bR to reduce chronic inflammation. Address correspondence and reprint requests to Dr. David M. Mosser, Cell Biology and Molecular Genetics, 3102 Bioscience Research Building, 4066 Campus Drive, Materials and Methods University of Maryland, College Park, MD 20742. E-mail address: [email protected] Mice and macrophage isolation The online version of this article contains supplemental material. Abbreviations used in this article: BMDM, bone marrow–derived macrophage; eATP, C57BL/6 mice were purchased from the Charles River Laboratories. These extracellular ATP; NECA, N-ethyl carboxamidoadenosine; Poly(I:C), polyinosinic- studies were reviewed and approved by the University of Maryland In- polycytidylic acid; qPCR, quantitative PCR; WT, wild type. stitutional Animal Care and Use Committee. Bone marrow–derived mac- rophages were prepared from 6–8-wk-old female C57BL/6, A2ar2/2 2 2 2 2 Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 (Jackson Labs), A2br / (12), or Stat1 / (Taconic) mice and their www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501139 The Journal of Immunology 3829 Downloaded from http://www.jimmunol.org/ by guest on October 1, 2021 FIGURE 1. IFN-g prolongs the macrophage activation state. (A and C) Cytokine production by LPS-stimulated unprimed (black squares, solid line) or IFN-g–primed (gray circles, solid line) BMDMs over time. (A) TNF-a and (C) IL-12/23p40 was detected with ELISA. The means 6 SEM of three in- dependent experiments are shown. (B and D) Unprimed (black squares, solid line) or IFN-g–primed (gray circles, solid line) BMDMs were stimulated with LPS and then washed with PBS (break in y-axis) and replaced with LPS-free media and monitored over the next 1–6 h for (B) TNF-a and (D) IL-12/23p40. (E) BMDMs were stimulated with LPS alone or in the presence of increasing doses of POM-1. Eight hours after stimulation, cytokine production was assessed with ELISA for TNF-a (black bars), IL-12/23p40 (dark gray bars), and IL-10 (light gray bars). The means 6 SEM of three experiments are shown. (F–I) Unprimed BMDMs (black bars) and IFN-g–primed BMDMs (gray bars) were stimulated with LPS for 4 h. (F) Il-10,(G) Arg1,(H) Il-33,and(I) Hmox-1 mRNA levels were determined with qPCR. The means 6 SEM of at least three independent experiments are shown. (J) WT (black bars) or STAT12/2 BMDMs (striped bars) were left unprimed or primed with IFN-g and then stimulated with LPS. TNF-a (left) and IL-12/23p40 (right) were measured in the supernatants 8 h after stimulation. Protein was measured by ELISA. The means 6 SD of triplicates are shown. **p , 0.01, ***p , 0.001. 3830 THE DOWNREGULATION OF A2bR BY IFN-g respective littermate controls, as described previously (13) and differen- addition of 10 ng/ml Ultra-Pure LPS with or without 108 cells/ml heat- tiated in 20% L929 (LC14) conditioned media unless noted otherwise. killed L. monocytogenes,0.5mg/ml Pam3CSK4, 0.5 mg/ml Poly(I:C)
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