Premium
The human G protein‐coupled ATP receptor P2Y 11 is a target for anti‐inflammatory strategies
Author(s) -
Gruenbacher Georg,
Gander Hubert,
Dobler Gabriele,
Rahm Andrea,
Klaver Dominik,
Thurnher Martin
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15379
Subject(s) - receptor , microbiology and biotechnology , p2 receptor , biology , p2y receptor , ppads , inflammation , protease activated receptor 2 , endocrinology , 5 ht5a receptor , agonist , immunology , biochemistry
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.