Damage response signaling by the extracellular adenosine pathway: control of infection outcome during host aging

In response to damage triggered by various stimuli including infections, ATP is released from damaged cells and converted to adenosine in the extracellular space by the ectonucleotidases CD39 and CD73. Extracellular adenosine is an immune modulatory molecule that signals via four G-protein receptors: A1, A2A, A2B, and A3, which can have opposing downstream effects on immune responses. In this minireview, we follow up on our mSphere of Influence commentary that focused on the A2B receptor (2019) to give a broader view of the role of the extracellular adenosine signaling pathway in host defense against infections. Studies demonstrate that extracellular adenosine serves as a key signaling molecule regulating the balance between effective pathogen clearance and immunopathology during infection. Extracellular adenosine displays dose- and time-dependent roles during infection, with individual adenosine receptors playing specific roles in controlling immune responses. Age-driven changes in this pathway contribute to the increased susceptibility of older hosts to certain infections, although there are several key unanswered questions about the role of the extracellular adenosine pathway in immunosenescence. Clinical and translational findings reveal a role for extracellular adenosine production and signaling in infections in humans, and there have been recent advances, but several ongoing challenges remain in pharmacologically targeting this pathway to reshape host immune responses.