A P2Y Receptor survey identifies P2Y11 as an immunomodulatory and antiviral protein in macrophages

The immune system is in place to assist in ensuring tissue homeostasis, which can easily be perturbed by invading pathogens or non-pathogenic stressors causing tissue damage. Extracellular nucleotides are well-known to contribute to innate immune signaling specificity and strength, but how their signaling is relayed downstream of cell surface receptors and how this translates into antiviral immunity is only partially understood. We systematically investigated macrophage responses to extracellular nucleotides focusing on the P2Y receptor family. Time-resolved transcriptomic analysis showed that adenine- and uridine-based nucleotides induce a specific, immediate and transient cytokine response through the MAPK signaling pathway regulation of AP-1 transcriptional activation. Using receptor trans-complementation, we identified a subset of P2Ys (P2Y1, P2Y2, P2Y6 and P2Y11) that governs the cytokine induction, while others (P2Y4, P2Y11, P2Y12, P2Y13 and P2Y14) directly induce antiviral responses. Notably, P2Y11 combined both activities and depletion or inhibition of this receptor in macrophages impaired both inflammatory and antiviral responses. Collectively, our study provides in-depth characterization of the underappreciated functions of P2Y receptors in innate immune processes.