A2A adenosine receptor activation prevents neutrophil aging and promotes polarization from N1 towards N2 phenotype

Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent immunosuppressive effects by binding to and activating G protein-coupled A 2A adenosine receptors (A 2A ARs) on the surface of neutrophils. A 2A AR signaling reproduces many of the phenotypic changes in neutrophils that are characteristic of sepsis, including decreased degranulation, impaired chemotaxis, and diminished ability to ingest and kill bacteria. We hypothesized that A 2A ARs also suppress neutrophil aging, which precedes cell death, and N1 to N2 polarization. Using human neutrophils isolated from healthy subjects, we demonstrate that A 2A AR stimulation slows neutrophil aging, suppresses cell death, and promotes the polarization of neutrophils from an N1 to N2 phenotype. Using genetic knockout and pharmacological blockade, we confirmed that A 2A ARs decrease neutrophil aging in murine sepsis induced by cecal ligation and puncture. A 2A ARs expression is increased in neutrophils from septic patients compared to healthy subject but A 2A AR expression fails to correlate with aging or N1/N2 polarization. Our data reveals that A 2A ARs regulate neutrophil aging in healthy but not septic neutrophils.