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

Area of Science:

• Immunology
• Molecular Biology
• Cell Signaling

Background:

• The immune system maintains tissue homeostasis, but can be disrupted by pathogens and stressors.
• Extracellular nucleotides are known to modulate innate immunity, yet downstream signaling and antiviral roles are unclear.
• Understanding nucleotide signaling is crucial for deciphering immune responses to tissue damage and infection.

Purpose of the Study:

• To systematically investigate human macrophage responses to extracellular nucleotides.
• To elucidate the role of G protein-coupled receptors (GPCRs) of the P2Y family in innate immunity.
• To define the specific contributions of different P2Y receptors to inflammatory and antiviral immunity.

Main Methods:

• Time-resolved transcriptomic analysis of human macrophages stimulated with nucleotides.
• Investigation of signaling pathways, including MAPK and AP-1 transcriptional activation.
• Receptor trans-complementation assays to identify functional P2Y receptor roles.

Main Results:

• Adenine- and uridine-based nucleotides induced rapid, transient cytokine responses via MAPK and AP-1.
• Specific P2Y receptors (P2Y1, P2Y2, P2Y6) mediated inflammatory cytokine induction.
• Other P2Y receptors (P2Y4, P2Y11, P2Y12, P2Y13, P2Y14) directly induced antiviral responses.
• P2Y11 exhibited dual activity, mediating both inflammatory and antiviral functions.
• Depletion or inhibition of P2Y11 impaired both inflammatory and antiviral macrophage responses.

Conclusions:

• P2Y receptors are critical regulators of innate immune responses to extracellular nucleotides.
• Distinct P2Y receptors orchestrate specific inflammatory and antiviral signaling cascades.
• P2Y11 is a key receptor with a dual role in macrophage-mediated immunity.