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Plaque‐like A3 Adenosine Receptor Microdomains Are Associated with Bacteria‐Tethering Nanotubes in Human Neutrophils

Using the fluorescent A3AR ligand CA200645, in conjunction with confocal microscopy and flow cytometry, we show here that endogenous adenosine receptors accumulate in plaque‐like microdomains on the surface of human neutrophils and neutrophil‐like HL60 cells. Studies with HL60 cells expressing an RFP‐tagged actin‐binding protein (LifeAct) revealed that the adenosine receptor plaques are strongly co‐localized with actin‐rich leading‐edge protrusions. In human neutrophils, pre‐incubation with the selective A3AR antagonist MRS1334 blocked the binding of the fluorescent ligand, indicating that these plaques are composed predominantly of A3ARs. MRS1334 also significantly inhibited the chemotaxis of human neutrophils in the presence of the chemoattractant fMLP, slowing the average migration speed from 5.47 ± 0.30 to 2.29 ± 0.19 μm/min. In addition to their involvement in chemotaxis, A3AR plaques were found at the base of nanotubes that extend from the plasma membranes of neutrophils in the presence of bacteria. These structures can reach in excess of 80 μm in length and are capable of tethering and “reeling in” bacteria for subsequent phagocytosis. Together, this evidence suggests that A3AR plaques act as chemosensory domains in human neutrophils; these domains facilitate cell migration and are associated with nanotubes, which enable the neutrophils to phagocytose pathogens in a rapid, targeted fashion.