biostudies-literatureAndersen LLDeutsche Forschungsgemeinschaft (DFG)Elitenetzwerk BayernBavarian State Ministry of Education, Science and the Arts | Elitenetzwerk Bayern (ENB)The Helmholtz Association's Initiative and Networking FundDeutsche ForschungsgemeinschaftEuropean Research Councile113279https://www.ebi.ac.uk/biostudies/studies/S-EPMC10690470biostudies-literatureUnknown42(23)The immune system is in place to assist in ensuring tissue homeostasis, which can be easily perturbed by invading pathogens or nonpathogenic 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. Here, we systematically investigated the responses of human macrophages to extracellular nucleotides, focusing on the nucleotide-sensing GPRC receptors of the P2Y 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 that regulaThe EMBO journalSystematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages.PMC10690470For COVID817798CRC179 (Project‐ID272983813) (to A.P. TP11)786602Pro DAP (817798)CRC353 (Project-ID471011418) (to A.P. B04)CRC237 (Project‐ID369799452) (A07 to A.P., A27 to V.H., B14 to A.K.)CRC179 (Project-ID272983813) (to A.P. TP11)CRC237 (Project-ID369799452) (A07 to A.P., A27 to V.H., B14 to A.K.)PI 1084/5PI 1084/7ENVISION (786602)CRC353 (Project‐ID471011418) (to A.P. B04)PI 1084/4COVIPA (KA1-Co-02)Hornung VWinheim EOubraham LKrug AEngleitner TPaludan SRO'Duill FEbert THuang YRad RUrban CStafford CNagl DPichlmair AAndersen LLfalseSystematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages.The immune system is in place to assist in ensuring tissue homeostasis, which can be easily perturbed by invading pathogens or nonpathogenic 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. Here, we systematically investigated the responses of human macrophages to extracellular nucleotides, focusing on the nucleotide-sensing GPRC receptors of the P2Y 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 that regula2023-01-01T00:00:00Z2023 Dec2025-04-19T14:10:36.651Z2025-04-19T14:10:36.651ZS-EPMC106904703788115510.15252/embj.2022113279