The human G protein‐coupled ATP receptor P2Y(11) is a target for anti‐inflammatory strategies

BACKGROUND AND PURPOSE: The ATP receptor P2Y(11), which couples to G(q) and G(s) proteins, senses cell stress and promotes cytoprotective responses. P2Y(11) receptors are upregulated during differentiation of M2 macrophages. However, it is unclear whether and how P2Y(11) receptors contribute to the anti‐inflammatory properties of M2 macrophages. EXPERIMENTAL APPROACH: Transcriptome and secretome profiling of ectopic P2Y(11) receptors was used to analyse their signalling and function. Findings were validated in human monocyte‐derived M2 macrophages. The suramin analogue NF340 and P2Y(11) receptor‐knockout cells confirmed that agonist‐mediated responses were specific to P2Y(11) receptor stimulation. KEY RESULTS: Temporal transcriptome profiling of P2Y(11) receptor stimulation showed a strong and tightly controlled response of IL‐1 receptors, including activation of the IL‐1 receptor target genes, IL6 and IL8. Secretome profiling confirmed the presence of IL‐6 and IL‐8 proteins and additionally identified soluble tumour necrosis factor receptor 1 and 2 (sTNFR1 and sTNFR2) as targets of P2Y(11) receptor activation. Raised levels of intracellular cAMP in M2 macrophages, after inhibition of phosphodiesterases (PDE), especially PDE4, strongly increased P2Y(11) receptor‐induced release of sTNFR2 through ectodomain shedding mediated by TNF‐α converting enzyme (TACE/ADAM17). Both IL‐1α and IL‐1ß synergistically enhanced P2Y(11) receptor‐ induced IL‐6 and IL‐8 secretion and release of sTNFR2. During lipopolysaccharide‐induced activation of TLR4, which shares the downstream signalling pathway with IL‐1 receptors, P2Y(11) receptors specifically prevented secretion of TNF‐α. CONCLUSIONS AND IMPLICATIONS: Targeting P2Y(11) receptors activates IL‐1 receptor signalling to promote sTNFR2 release and suppress TLR4 signalling to prevent TNF‐α secretion, thus facilitating resolution of inflammation.