Systematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages

Abstract

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 regulates transcriptional activation by AP‐1. Using receptor trans‐complementation, we identified a subset of P2Ys (P2Y1, P2Y2, P2Y6, and P2Y11) that govern inflammatory responses via 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, these results highlight the underappreciated functions of P2Y receptors in innate immune processes.

Deficiency of P2RY11 causes narcolepsy and attenuates the recruitment of neutrophils and macrophages in the inflammatory response in zebrafish

“…The activation of P2Y11 reduced the increase in TNF-α induced by radiation and increased IL-10 release in the blood (Swennen et al 2008 ). Recent evidence shows that P2Y11 functions as a key receptor for macrophages, playing a vital role in regulating cytokine expression and inhibiting virus replication upon nucleotide interactions (Andersen et al 2023 ). However, almost all studies on the function of P2Y11 have only been conducted in various cell lines because the P2Y11 gene is absent in rodents.…”