Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation

Woehrle, Tobias; Ledderose, Carola; Rink, Jessica; Slubowski, Christian J.; Junger, Wolfgang G.

doi:10.1007/s11302-019-09653-6

Cited by 20 publications

(14 citation statements)

References 42 publications

(73 reference statements)

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“…In order to study whether P2Y11 receptors are involved in Ca 2+ signaling during T cell stimulation, we loaded human CD4 cells with the cytosolic Ca 2+ probe Fluo-4 AM that allows real-time monitoring of intracellular Ca 2+ levels using live-cell fluorescence microscopy. In agreement with previous reports,18,33 we found that inhibition of P2X4 receptors completely abolished the Ca 2+ signaling response to cell stimulation by TCR/CD28 crosslinking (Fig. 2A, B).…”

supporting

confidence: 93%

Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse

Ledderose

Bromberger

Slubowski

et al. 2020

Journal of Leukocyte Biology

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T cells form an immune synapse (IS) with antigen-presenting cells (APCs) to detect antigens that match their TCR. Mitochondria, pannexin-1 (panx1) channels, and P2X4 receptors congregate at the IS where mitochondria produce the ATP that panx1 channels release in order to stimulate P2X4 receptors. P2X4 receptor stimulation causes cellular Ca 2+ influx that up-regulates mitochondrial metabolism and localized ATP production at the IS. Here we show that P2Y11 receptors are essential players that sustain these T cell activation mechanisms. We found that P2Y11 receptors retract from the IS toward the back of cells where their stimulation by extracellular ATP induces cAMP/PKA signaling that redirects mitochondrial trafficking to the IS. P2Y11 receptors thus reinforce IS signaling by promoting the aggregation of mitochondria with panx1 ATP release channels and P2X4 receptors at the IS. This dual purinergic signaling mechanism involving P2X4 and P2Y11 receptors focuses mitochondrial metabolism to the IS where localized ATP production sustains synaptic activity in order to allow successful completion of T cell activation responses. Our findings have practical implications because rodents lack P2Y11 receptors, raising concerns as to the validity of rodent models to study treatment of infections and inflammatory conditions.

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supporting

confidence: 93%

Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse

Ledderose

Bromberger

Slubowski

et al. 2020

Journal of Leukocyte Biology

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“…Recently, Woehrle T et al found that P2Y1R could regulate T cell function. It found that exogenous ADP or overexpression of P2Y1R could dramatically increase mRNA transcription of IL-2 in response to TCR/CD28 stimulation, and antagonists or silencing of P2Y1R could reduce mRNA transcription of IL-2 and mitochondrial Ca 2+ uptake in stimulated CD4 + T cells (15). However, the role of P2Y1R in regulation of adaptive immunity still remains largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

“…P2Y1R is a Gα q/11 ADP receptor, which is abundant in nearly all human and rodent tissues ( 14 ). Besides its key role in the nervous system, P2Y1R also exerts potent immunity such as leading NLRP3 inflammasome priming and facilitating T cell activation in an ERK-dependent manner ( 13 , 15 ). However, its function in regulation of Th17 cells is still unclear.…”

Section: Introductionmentioning

confidence: 99%

P2Y1R Ligation Suppresses Th17 Cell Differentiation and Alleviates Colonic Inflammation in an AMPK-Dependent Manner

et al. 2022

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P2Y1 receptor is a G-protein-coupled receptor that plays a critical role in the immune response of inflammatory bowel diseases. However, its regulatory effects on CD4+ T cell response have not been fully elucidated. The study aimed to characterize the role of P2Y1R in Th17 cell differentiation and colonic inflammation. Our results demonstrated that P2Y1R was significantly increased in the splenocytes of colitic mice, which was positively associated with the expression of RORγt and IL-17A. P2Y1R deficiency significantly ameliorated DSS-induced colitis and its Th17 responses. In parallel, P2Y1R deficiency greatly impaired the differentiation of Th17 cell, down-regulated the mRNA expression of IL-17A and RORγt, and protein expression of RORγt in vitro. More importantly, it was found that P2Y1R deficiency markedly increased AMPK phosphorylation of Th17 polarized CD4+ T cells, and antagonist of AMPK significantly reversed the inhibitory effect of P2Y1R deficiency on Th17 cell generation in vivo and in vitro. Overall, these findings demonstrated that P2Y1R deficiency could suppress Th17 cell differentiation in an AMPK-dependent manner to ameliorate colitis, and P2Y1R can act as an important regulator of Th17 cell differentiation to control colonic inflammation.

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“…Future studies will be required to determine the precise mechanism by which IVM modulates P2Y1 activity. One possibility is that IVM may augment P2X-P2Y1 crosstalk to drive insulin secretion, which has been shown to drive Ca 2+ and P2Y1-dependent activation of other cell types (52,63).…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic rescue of circadian β-cell failure through P2Y1 purinergic receptor identified by small-molecule screen

Marcheva

Weidemann

Taguchi

et al. 2021

Preprint

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SummaryThe mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. However, identification of druggable proteins and pathways to ameliorate the burden of circadian metabolic disease remains a challenge. Here, we generated β cells expressing a nano-luciferase reporter within the proinsulin polypeptide to screen 2,640 pharmacologically-active compounds and identify insulinotropic molecules that bypass the secretory defect in clock mutant β cells. We validated lead compounds in primary mouse islets and identified known modulators of ligandgated ion channels and G-protein coupled receptors, including the antihelmintic ivermectin. Single-cell electrophysiology in circadian mutant mouse and human cadaveric islets validated ivermectin as a glucose-dependent secretagogue. Genetic, genomic, and pharmacologic analyses established that the molecular clock controls the expression of the purinergic P2Y1 receptor to mediate the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a target to rescue circadian β-cell failure and establish a chemical genetic screen for endocrine therapeutics.

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Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation

Cited by 20 publications

References 42 publications

Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse

Frontline Science: P2Y11 receptors support T cell activation by directing mitochondrial trafficking to the immune synapse

P2Y1R Ligation Suppresses Th17 Cell Differentiation and Alleviates Colonic Inflammation in an AMPK-Dependent Manner

Pharmacologic rescue of circadian β-cell failure through P2Y1 purinergic receptor identified by small-molecule screen

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