The human G protein‐coupled ATP receptor P2Y<sub>11</sub> is a target for anti‐inflammatory strategies

Gruenbacher, Georg; Gander, Hubert; Dobler, Gerhard; Rahm, Andrea; Klaver, Dominik; Thurnher, Martin

doi:10.1111/bph.15379

Cited by 13 publications

(54 citation statements)

References 54 publications

(85 reference statements)

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“…Accordingly, P2Y 11 activation with ATPγS effectively inhibited TNF-α production in LPS-activated macrophages, an effect that could be completely prevented by the P2Y 11 antagonist NF340. Our data thus indicate that P2Y 11 signaling via a G s -AC-cAMP axis blocks TNF-α secretion and promotes the release of sTNFR2 in human M2 macrophages (Figure 2), facilitating the resolution of inflammation [97].…”

Section: P2y 11 Receptormentioning

confidence: 64%

“…The recent finding that P2Y 14 receptors support inflammatory gene expression during TLR-induced macrophage activation confirms this view [136]. However, this concept has been challenged by a recent study, demonstrating that anti-inflammatory P2Y 11 receptor signaling controls TNF-α driven inflammation [97]. P2Y 11 is in many ways an unconventional member of the P2Y family of G protein-coupled receptors.…”

Section: Discussionmentioning

confidence: 98%

“…Consistent with earlier findings in dendritic cells [90,96], P2Y 11 receptor activation in M2 macrophages induced CXCL8 secretion. We extended these studies and performed the first transcriptomic and secretomic analyses of P2Y 11 receptor activation using an ectopic expression system [97]. The transcriptional network analyses revealed the signature of a strong but transient interleukin-1 receptor (IL-1R)/toll-like receptor (TLR) response, including activation of the IL-1R/TLR target genes IL6 and IL8.…”

Section: P2y 11 Receptormentioning

confidence: 99%

“…It is possible that P2Y 11 expression in GM-CSF differentiated human monocytes is actually driven by M-CSF, because GM-CSF induces M-CSF production in monocytes [101]. By blocking TNF-α secretion and by promoting sTNFR2 release, P2Y 11 may act as a sentinel in the surveillance of TNF-α driven inflammation [97]. P2Y 11 thus represents a target for antiinflammatory strategies in the treatment of autoimmune or infectious diseases.…”

Section: P2y 11 Receptormentioning

confidence: 99%

“…[101]. By blocking TNF-α secretion and by promoting sTNFR2 release, P2Y11 may act as a sentinel in the surveillance of TNF-α driven inflammation [97]. P2Y11 thus represents a target for anti-inflammatory strategies in the treatment of autoimmune or infectious diseases.…”

Section: P2y 11 Receptormentioning

confidence: 99%

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Control of Macrophage Inflammation by P2Y Purinergic Receptors

Klaver

Thurnher

2021

Cells

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Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy.

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Section: P2y 11 Receptormentioning

confidence: 64%

Section: Discussionmentioning

confidence: 98%

Section: P2y 11 Receptormentioning

confidence: 99%

Section: P2y 11 Receptormentioning

confidence: 99%

Section: P2y 11 Receptormentioning

confidence: 99%

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Control of Macrophage Inflammation by P2Y Purinergic Receptors

Klaver

Thurnher

2021

Cells

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Heterogeneity in extracellular vesicle secretion by single human macrophages revealed by super‐resolution microscopy

Dechantsreiter

Ambrose

Worboys

et al. 2022

J of Extracellular Vesicle

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The diverse origins, nanometre-scale and invasive isolation procedures associated with extracellular vesicles (EVs) mean they are usually studied in bulk and disconnected from their parental cell. Here, we used super-resolution microscopy to directly compare EVs secreted by individual human monocyte-derived macrophages (MDMs). MDMs were differentiated to be M0-, M1-or M2-like, with all three secreting EVs at similar densities following activation. However, M0-like cells secreted larger EVs than M1-and M2-like macrophages. Proteomic analysis revealed variations in the contents of differently sized EVs as well as between EVs secreted by different MDM phenotypes. Super resolution microscopy of single-cell secretions identified that the class II MHC protein, HLA-DR, was expressed on ∼40% of EVs secreted from M1-like MDMs, which was double the frequency observed for M0-like and M2like EVs. Strikingly, human macrophages, isolated from the resected lungs of cancer patients, secreted EVs that expressed HLA-DR at double the frequency and with greater intensity than M1-like EVs. Quantitative analysis of single-cell EV profiles from all four macrophage phenotypes revealed distinct secretion types, five of which were consistent across multiple sample cohorts. A sub-population of M1-like MDMs secreted EVs similar to lung macrophages, suggesting an expansion or recruitment of cells with a specific EV secretion profile within the lungs of cancer patients. Thus, quantitative analysis of EV heterogeneity can be used for single cell profiling and to reveal novel macrophage biology.

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The P2Y11 receptor of human M2 macrophages activates canonical and IL-1 receptor signaling to translate the extracellular danger signal ATP into anti-inflammatory and pro-angiogenic responses

Klaver

Gander

Dobler

et al. 2022

Cell. Mol. Life Sci.

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The cytoprotective ATP receptor P2Y 11 is upregulated during M2 macrophage differentiation and contributes to the anti-inflammatory properties of this macrophage subset. Here, we studied P2Y 11 -induced reprogramming of human M2 macrophages at the level of mRNA and protein expression. Upregulation of IL-1 receptor (IL-1R) and its known downstream effectors VEGF, CCL20 and SOCS3 as well as downregulation of the ATP-degrading ecto-ATPase CD39 emerged as hallmarks of P2Y 11 activation. The anti-inflammatory signature of the P2Y 11 transcriptome was further characterized by the downregulation of P2RX7, toll-like receptors and inflammasome components. P2Y 11 -induced IL-1R upregulation formed the basis for reinforced IL-1 responsiveness of activated M2 macrophages, as IL-1α and IL-1ß each enhanced P2Y 11 -induced secretion of VEGF and CCL20 as well as the previously reported shedding of soluble tumor necrosis factor receptor 2 (sTNFR2). Raising intracellular cyclic AMP (cAMP) in M2 macrophages through phosphodiesterase 4 inhibition enhanced P2Y 11 -driven responses. The cAMP-binding effector, exchange protein activated by cAMP 1 (Epac1), which is known to induce SOCS3, differentially regulated the P2Y 11 /IL-1R response because pharmacological Epac1 inhibition enhanced sTNFR2 and CCL20 release, but had no effect on VEGF secretion. In addition to cAMP, calcium and protein kinase C participated in P2Y 11 signaling. Our study reveals how P2Y 11 harnesses canonical and IL-1R signaling to promote an anti-inflammatory and pro-angiogenic switch of human M2 macrophages, which may be controlled in part by an Epac1-SOCS3 axis. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-022-04548-z.

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

Cited by 13 publications

References 54 publications

Control of Macrophage Inflammation by P2Y Purinergic Receptors

Control of Macrophage Inflammation by P2Y Purinergic Receptors

Heterogeneity in extracellular vesicle secretion by single human macrophages revealed by super‐resolution microscopy

The P2Y11 receptor of human M2 macrophages activates canonical and IL-1 receptor signaling to translate the extracellular danger signal ATP into anti-inflammatory and pro-angiogenic responses

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

Cited by 13 publications

References 54 publications

Control of Macrophage Inflammation by P2Y Purinergic Receptors

Control of Macrophage Inflammation by P2Y Purinergic Receptors

Heterogeneity in extracellular vesicle secretion by single human macrophages revealed by super‐resolution microscopy

The P2Y11 receptor of human M2 macrophages activates canonical and IL-1 receptor signaling to translate the extracellular danger signal ATP into anti-inflammatory and pro-angiogenic responses

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