The purinergic receptor P2Y11 choreographs the polarization, mitochondrial metabolism, and migration of T lymphocytes

Ledderose, Carola; Bromberger, Sophie; Slubowski, Christian J.; Sueyoshi, Koichiro; Aytan, Dilan; Shen, Yong; Junger, Wolfgang G.

doi:10.1126/scisignal.aba3300

Cited by 42 publications

(27 citation statements)

References 67 publications

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“…ATPγS, similar to ATP, is likely to induce internalization of the P2Y11 receptor. The lack of expression or functional P2Y11 receptor in the breast cancer cells reduces breast cancer migration, indicating the intrinsic activity of this receptor, as reported in other cellular systems [ 46 , 47 ].…”

Section: Discussionmentioning

confidence: 55%

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ATP Inhibits Breast Cancer Migration and Bone Metastasis through Down-Regulation of CXCR4 and Purinergic Receptor P2Y11

Liu

Riquelme²,

Tian

et al. 2021

Cancers

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ATP released by bone osteocytes is shown to activate purinergic signaling and inhibit the metastasis of breast cancer cells into the bone. However, the underlying molecular mechanism is not well understood. Here, we demonstrate the important roles of the CXCR4 and P2Y11 purinergic receptors in mediating the inhibitory effect of ATP on breast cancer cell migration and bone metastasis. Wound-healing and transwell migration assays showed that non-hydrolysable ATP analogue, ATPγS, inhibited migration of bone-tropic human breast cancer cells in a dose-dependent manner. BzATP, an agonist for P2X7 and an inducer for P2Y11 internalization, had a similar dose-dependent inhibition on cell migration. Both ATPγS and BzATP suppressed the expression of CXCR4, a chemokine receptor known to promote breast cancer bone metastasis, and knocking down CXCR4 expression by siRNA attenuated the inhibitory effect of ATPγS on cancer cell migration. While a P2X7 antagonist A804598 had no effect on the impact of ATPγS on cell migration, antagonizing P2Y11 by NF157 ablated the effect of ATPγS. Moreover, the reduction in P2Y11 expression by siRNA decreased cancer cell migration and abolished the impact of ATPγS on cell migration and CXCR4 expression. Similar to the effect of ATPγS on cell migration, antagonizing P2Y11 inhibited bone-tropic breast cancer cell migration in a dose-dependent manner. An in vivo study using an intratibial bone metastatic model showed that ATPγS inhibited breast cancer growth in the bone. Taken together, these results suggest that ATP inhibits bone-tropic breast cancer cells by down-regulating the P2Y11 purinergic receptor and the down-regulation of CXCR4 expression.

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Section: Discussionmentioning

confidence: 55%

“…P2Y11 is also involved in the anti-tumor process of ATP in prostate cancer DU145 cells [ 45 ]. Another study reported that over stimulation of P2Y11 with excessive extracellular ATP results in defective T cell migration [ 46 ]. Therefore, we explored the role of P2Y11 in the effect of ATPγS on breast cancer cell migration.…”

Section: Discussionmentioning

confidence: 99%

ATP Inhibits Breast Cancer Migration and Bone Metastasis through Down-Regulation of CXCR4 and Purinergic Receptor P2Y11

Liu

Riquelme²,

Tian

et al. 2021

Cancers

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“…In the continuation of their previous work, Ledderose et al studied the role of the purinergic receptor P2Y11 in the migration of human T lymphocytes (97). The P2Y11 receptor is a G-protein coupled receptor which, after binding of extracellular ATP, induces the production of the second messenger c-AMP, which stimulates protein-kinase A.…”

Section: Role Of P2x4 In T Cell Receptor Signaling and T Cell Migrationmentioning

confidence: 95%

Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective

et al. 2021

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Extracellular nucleotides are important mediators of activation, triggering various responses through plasma membrane P2 and P1 receptors. P2 receptors are further subdivided into ionotropic P2X receptors and G protein-coupled P2Y receptors. P2X4 is an ATP-gated cation channel broadly expressed in most tissues of the body. Within the P2X family, P2X4 has a unique subcellular distribution, being preferentially localized in lysosomes. In these organelles, high ATP concentrations do not trigger P2X4 because of the low pH. However, when the pH increases to 7.4, P2X4 can be stimulated by intra-lysosomal ATP, which is in its active, tetra-anionic form. Elucidation of P2X4, P2X3 and P2X7 structures has shed some light on the functional differences between these purinergic receptors. The potential interaction between P2X4 and P2X7 has been extensively studied. Despite intensive effort, it has not been possible yet to determine whether P2X4 and P2X7 interact as heterotrimers or homotrimers at the plasma membrane. However, several publications have shown that functional interactions between P2X4 and P2X7 do occur. Importantly, these studies indicate that P2X4 potentiates P2X7-dependent activation of inflammasomes, leading to increased release of IL-1β and IL-18. The role of P2X4 in various diseases could be beneficial or deleterious even though the pathophysiological mechanisms involved are still poorly defined. However, in diseases whose physiopathology involves activation of the NLRP3 inflammasome, P2X4 was found to exacerbate severity of disease. The recent production of monoclonal antibodies specific for the human and mouse P2X4, some of which are endowed with agonist or antagonist properties, raises the possibility that they could be used therapeutically. Analysis of single nucleotide polymorphisms of the human P2RX4 gene has uncovered the association of P2RX4 gene variants with susceptibility to several human diseases.

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“…P2Y 11 receptor expression is often associated with immune cells. P2Y 11 receptors have recently been shown to participate in the process of T cell migration by regulating mitochondrial metabolism [ 95 ]. In addition to T cells, which are components of the adaptive immune system, P2Y 11 receptor expression has repeatedly been reported to occur in innate immune cells [ 25 , 61 , 90 , 91 , 93 , 96 ].…”

Section: P2y 11 Receptormentioning

confidence: 99%

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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The purinergic receptor P2Y11 choreographs the polarization, mitochondrial metabolism, and migration of T lymphocytes

Cited by 42 publications

References 67 publications

ATP Inhibits Breast Cancer Migration and Bone Metastasis through Down-Regulation of CXCR4 and Purinergic Receptor P2Y11

ATP Inhibits Breast Cancer Migration and Bone Metastasis through Down-Regulation of CXCR4 and Purinergic Receptor P2Y11

Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective

Control of Macrophage Inflammation by P2Y Purinergic Receptors

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