The human G protein-coupled ATP receptor P2Y₁₁ is a target for anti-inflammatory strategies

The ATP receptor P2Y₁₁ , which couples to G_q and G_s proteins, senses cell stress and promotes cytoprotective responses. P2Y₁₁ receptors are upregulated during differentiation of M2 macrophages. However, it is unclear whether and how P2Y₁₁ receptors contribute to the anti-inflammatory properties of M2 macrophages.

Transcriptome and secretome profiling of ectopic P2Y₁₁ receptors was used to analyse their signalling and function. Findings were validated in human monocyte-derived M2 macrophages. The suramin analogue NF340 and P2Y₁₁ receptor-knockout cells confirmed that agonist-mediated responses were specific to P2Y₁₁ receptor stimulation.

Temporal transcriptome profiling of P2Y₁₁ 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 P2Y₁₁ receptor activation. Raised levels of intracellular cAMP in M2 macrophages, after inhibition of phosphodiesterases (PDE), especially PDE4, strongly increased P2Y₁₁ receptor-induced release of sTNFR2 through ectodomain shedding mediated by TNF-α converting enzyme (TACE/ADAM17). Both IL-1α and IL-1ß synergistically enhanced P2Y₁₁ 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, P2Y₁₁ receptors specifically prevented secretion of TNF-α.

Targeting P2Y₁₁ receptors activates IL-1 receptor signalling to promote sTNFR2 release and suppress TLR4 signalling to prevent TNF-α secretion, thus facilitating resolution of inflammation.