ArticleJournal of immunology (Baltimore, Md. : 1950)2015
IFN-γ Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response.
Article in Journal of immunology (Baltimore, Md. : 1950), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
- Enhanced antitumor efficacy of combined targeting of adenosine ACancer immunology, immunotherapy : CII · 2026Article
- Neoantigen mRNA vaccines and AHuman vaccines & immunotherapeutics · 2025Review
- APurinergic signalling · 2025Review
- Adenosine signaling in tumor-associated macrophages and targeting adenosine signaling for cancer therapy.Cancer biology & medicine · 2024Review
- The Role of Cluster of Differentiation 39 (CD39) and Purinergic Signaling Pathway in Viral Infections.Pathogens (Basel, Switzerland) · 2023Review
- The ectonucleotidases CD39 and CD73 on T cells: The new pillar of hematological malignancy.Frontiers in immunology · 2023Review
- The adenosinergic machinery in cancer: In-tandem insights from basic mechanisms to therapy.Frontiers in immunology · 2023Review
- Review
- Macrophage inflammatory state influences susceptibility to lysosomal damage.Journal of leukocyte biology · 2022Article
- Purinergic modulation of the immune response to infections.Purinergic signalling · 2022Review
- TLR ligand ligation switches adenosine receptor usage of BMDCs leading to augmented Th17 responses in experimental autoimmune uveitis.Current research in immunology · 2022Article
- Immunosuppressive adenosine-targeted biomaterials for emerging cancer immunotherapy.Frontiers in immunology · 2022Review
- ATP and cancer immunosurveillance.The EMBO journal · 2021Review
- Adenosine Signaling in Mast Cells and Allergic Diseases.International journal of molecular sciences · 2021Review
- Targeting CD39 in cancer.Nature reviews. Immunology · 2020Review
- The adenosine pathway in immuno-oncology.Nature reviews. Clinical oncology · 2020Review
- Adenosine Signaling in Autoimmune Disorders.Pharmaceuticals (Basel, Switzerland) · 2020Review
- On the mechanism of anti-CD39 immune checkpoint therapy.Journal for immunotherapy of cancer · 2020Review
- AInternational journal of molecular sciences · 2019Review
- Targeting A2 adenosine receptors in cancer.Immunology and cell biology · 2017Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.