Adenosine Signaling in Immune and Inflammatory Responses
Summary
Adenosine is a purine nucleoside that accumulates extracellularly under conditions of cellular stress, hypoxia or tissue damage. It is generated by the stepwise dephosphorylation of ATP and ADP via the ectonucleotidases CD39 and CD73. Extracellular adenosine signals through four G protein–coupled P1 receptors—A1, A2A, A2B and A3—to orchestrate immune and inflammatory pathways. Engagement of the A2A receptor on macrophages, neutrophils and dendritic cells elevates intracellular cAMP, leading to the suppression of pro-inflammatory cytokine release and oxidative burst. In the adaptive arm, A2A-mediated cAMP accumulation fosters regulatory T cell expansion while restraining effector T helper differentiation. In hypoxic or inflamed tissues, high adenosine concentrations contribute to an immunosuppressive microenvironment that hinders cytotoxic lymphocyte infiltration. Structural and pharmacological studies have revealed that A2B receptor activation can, in certain epithelial contexts, reinforce barrier integrity and promote resolution. Translational efforts now focus on modulating this axis with small-molecule inhibitors, monoclonal antibodies and engineered cell therapies. These interventions hold promise across cancer immunotherapy, autoimmunity, infectious disease and tissue repair, positioning adenosine signalling as a key metabolic checkpoint in immune regulation.
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Adenosine Signaling in Immune and Inflammatory Responses publication trend
The graph below shows the total number of articles in adenosine signaling in immune and inflammatory responses across all publications each year (not limited to Nature Index journals).
Technical terms
Adenosine: A purine nucleoside formed by dephosphorylation of extracellular ATP that modulates immune cell activation through P1 receptors.
Ectonucleotidases (CD39, CD73): Membrane-bound enzymes that catalyse the sequential removal of phosphate groups from extracellular nucleotides to generate adenosine.
A2A receptor (A2AR): A Gs-coupled adenosine receptor with high affinity for adenosine, which elevates intracellular cAMP to suppress immune effector functions.
cAMP: Cyclic adenosine monophosphate, a second messenger produced in response to G protein–coupled receptor activation, regulating diverse cellular processes.
Purinergic signalling: A cell communication network mediated by extracellular nucleotides (e.g., ATP, ADP) and nucleosides (e.g., adenosine) acting on P2 and P1 receptors, respectively.
References
- Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. Journal of Experimental Medicine (2007).
- A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Frontiers in Immunology (2016).
- CD39/CD73/A2AR pathway and cancer immunotherapy. Molecular Cancer (2023).
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