Human P2Y11 Expression Level Affects Human P2X7 Receptor-Mediated Cell Death

Dreisig, Karin; Sund, Louise; Dommer, Maja Wallentin; Kristensen, Nikolaj Pagh; Boddum, Kim; Viste, Rannveig; Fredholm, Simon; Ødum, Niels; Jäättelä, Marja; Skov, Søren; Kornum, Birgitte Rahbek

doi:10.3389/fimmu.2018.01159

Cited by 17 publications

(16 citation statements)

References 35 publications

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“…In earlier studies, P2Y 11 receptor involvement was suggested through detection of P2Y 11 receptor-encoding mRNA, by exclusion of other possible ATP receptors, and later by siRNA knockdown of the receptor to support pharmacological data, often related to cell survival and cytokine production as well as cell migration and differentiation (7–11). Functional P2Y 11 receptor expression has been reported in innate immune cells (1, 2) such as dendritic cells (DCs) (8, 9) and macrophages (12) as well as in adaptive immune cells (7, 13), strongly supporting its relevance in immune regulation.…”

Section: Introductionmentioning

confidence: 92%

The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation

et al. 2019

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The G protein-coupled P2Y 11 receptor is known to sense extracellular ATP during inflammatory and immune responses. The dinucleotide NAD + has also been proposed to be a P2Y 11 receptor ligand but its role is less clear. Here, we have examined for the first time human P2Y 11 receptor protein levels and show that the receptor was upregulated during polarization of M2 macrophages. IL-10 reinforced P2Y 11 receptor expression during differentiation of M2c macrophages expressing CD163, CD16, and CD274 (PD-L1). Nutlin-3a mediated p53 stabilization further increased P2Y 11 receptor, CD16, and PD-L1 expression. AMP-activated kinase (AMPK), which mediates anti-inflammatory effects of IL-10, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD + salvage pathway, which is under the control of AMPK, were also required for P2Y 11 receptor expression. The P2Y 11 receptor agonist ATPγS and NAD + could independently stimulate the production of IL-8 in M2 macrophages, however, only the ATPγS-induced response was mediated by P2Y 11 receptor. Both in a recombinant system and in macrophages, P2Y 11 receptor-driven IL-8 production predominantly depended on IkB kinase (IKK), and extracellular signal–regulated kinase (ERK). In conclusion, our data indicate that an AMPK-NAMPT-NAD + signaling axis promotes P2Y 11 receptor expression during M2 polarization of human macrophages in response to IL-10. PD-L1 expressing M2c macrophages that secrete the cancer-promoting chemokine IL-8 in response to P2Y 11 receptor stimulation may represent an important target in checkpoint blockade immunotherapy.

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Section: Introductionmentioning

confidence: 92%

The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation

et al. 2019

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“…Human T cells express A2a, A2b, A3, P2X1, P2X4, P2X5, and P2X7, as well as all eight P2Y receptor subtypes ( 34 – 36 ). P2X1, P2X4, P2Y11, and P2X7 receptors have particularly important roles in the regulation of CD4 T cells ( 10 – 12 , 36 – 40 ). Among these receptors, P2X1 receptors are most sensitive with an EC 50 value of 50-1000 nM ATP ( 22 , 41 ).…”

Section: P2x1 Receptors Maintain Mitochondrial Metabolism Of Quiescenmentioning

confidence: 99%

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function

Ledderose

Junger

2020

Front. Immunol.

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Intracellular ATP is the universal energy carrier that fuels many cellular processes. However, immune cells can also release a portion of their ATP into the extracellular space. There, ATP activates purinergic receptors that mediate autocrine and paracrine signaling events needed for the initiation, modulation, and termination of cell functions. Mitochondria contribute to these processes by producing ATP that is released. Here, we summarize the synergistic interplay between mitochondria and purinergic signaling that regulates T cell functions. Specifically, we discuss how mitochondria interact with P2X1, P2X4, and P2Y11 receptors to regulate T cell metabolism, cell migration, and antigen recognition. These mitochondrial and purinergic signaling mechanisms are indispensable for host immune defense. However, they also represent an Achilles heel that can render the host susceptible to infections and inflammatory disorders. Hypoxia and mitochondrial dysfunction deflate the purinergic signaling mechanisms that regulate T cells, while inflammation and tissue damage generate excessive systemic ATP levels that distort autocrine purinergic signaling and impair T cell function. An improved understanding of the metabolic and purinergic signaling mechanisms that regulate T cells may lead to novel strategies for the diagnosis and treatment of infectious and inflammatory diseases.

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“…According to the current view, P2Y 11 receptors sense extracellular ATP and translate this prototypical danger signal into cytoprotective and immunomodulatory responses (Kennedy, 2017;Vitiello et al, 2012). Expression of P2Y 11 receptors has been detected in immune (Dreisig et al, 2018;Marteau et al, 2005) and non-immune cells (Benoist et al, 2019;Lefort et al, 2018), including cancer cells (Khalid et al, 2017). Among immune cells, P2Y 11 receptors may preferentially be expressed in cells of myeloid origin such as dendritic cells (Schnurr et al, 2003;Wilkin et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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

Gruenbacher

Gander

Dobler

et al. 2021

British J Pharmacology

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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 receptorinduced IL-6 and IL-8 secretion and release of sTNFR2. During lipopolysaccharideinduced 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.

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Human P2Y11 Expression Level Affects Human P2X7 Receptor-Mediated Cell Death

Cited by 17 publications

References 35 publications

The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation

The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function

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

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Human P2Y11 Expression Level Affects Human P2X7 Receptor-Mediated Cell Death

Cited by 17 publications

References 35 publications

The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation

The Human G Protein-Coupled ATP Receptor P2Y11 Is Associated With IL-10 Driven Macrophage Differentiation

Mitochondria Synergize With P2 Receptors to Regulate Human T Cell Function

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

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