Systematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages.
P2YR
antiviral immunity
cytokine induction
innate immunity
nucleotide sensing
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
01 Dec 2023
01 Dec 2023
Historique:
revised:
20
09
2023
received:
14
12
2022
accepted:
29
09
2023
medline:
4
12
2023
pubmed:
26
10
2023
entrez:
26
10
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37881155
doi: 10.15252/embj.2022113279
pmc: PMC10690470
doi:
Substances chimiques
Cytokines
0
Nucleotides
0
P2RY11 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e113279Subventions
Organisme : Bavarian State Ministry of Education, Science and the Arts | Elitenetzwerk Bayern (ENB)
ID : For COVID
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : CRC237 (Project-ID369799452) (A07 to A.P., A27 to V.H., B14 to A.K.)
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : CRC179 (Project-ID272983813) (to A.P. TP11)
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : CRC353 (Project-ID471011418) (to A.P. B04)
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : PI 1084/4
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : PI 1084/5
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : PI 1084/7
Organisme : EC | European Research Council (ERC)
ID : Pro DAP (817798)
Organisme : EC | European Research Council (ERC)
ID : ENVISION (786602)
Organisme : The Helmholtz Association's Initiative and Networking Fund
ID : COVIPA (KA1-Co-02)
Informations de copyright
© 2023 The Authors. Published under the terms of the CC BY 4.0 license.
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