P2Y6 Receptor Contributes to Neutrophil Recruitment to Inflamed Intestinal Mucosa by Increasing Cxc Chemokine Ligand 8 Expression in an AP-1-dependent Manner in Epithelial Cells

Grbic, Djordje; Degagné, Émilie; Larrivée, Jean-François; Bilodeau, Maude S.; Vinette, Valérie; Arguin, Guillaume; Staňková, Jana; Gendron, Fernand‐Pierre

doi:10.1002/ibd.21931

Cited by 48 publications

(48 citation statements)

References 59 publications

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“…[12][13][14]16,18,19 However, the role of UDP and P2Y 6 in leukocyte recruitment to the inflamed vessel wall in vivo has not been addressed to date. To examine the latter, P2Y 6 -competent mice received peritoneal injections with 200 nmol UDP.…”

Section: Resultsmentioning

confidence: 99%

“…25,26 Administration of UDP aggravates colitis-like disease by inducing neutrophil recruitment to the bowel indicating an important role of UDP and P2Y 6 in inflammation. 19 Accordingly, in bacterial peritonitis, UDP injection results in a more efficacious clearance of Escherichia coli, suggesting again a proinflammatory role of the UDP-P2Y 6 axis. 16 In the present study, we provide evidence that UDP induces leukocyte rolling on and adhesion to inflamed vessels via P2Y 6 in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…12,16,18,19 Furthermore, pharmacological inhibition of P2Y 6 reduced the expression of the adhesion molecules VCAM-1 and ICAM-1 on an EC line after tumor necrosis factor-α stimulation, implicating that P2Y 6 contributes to leukocyte adhesion. 25,26 Administration of UDP aggravates colitis-like disease by inducing neutrophil recruitment to the bowel indicating an important role of UDP and P2Y 6 in inflammation.…”

Section: 22mentioning

confidence: 92%

“…Nuclei were stained with DAPI (4',6-diamidino-2-phenylindole; blue), endothelial for CD31 (green), and P2Y 6 (red). 13,18,19,21 To investigate the potential mechanisms of our findings that P2Y 6 deficiency limits atherogenesis, plaque inflammation, and inflammatory cell recruitment to the vessel wall, we evaluated the expression of these molecules in arterial tissue from P2Y 6 +/+ /LDLR −/− (n=5) and P2Y 6 −/− /LDLR −/− (n=4) mice after 16 weeks of high-cholesterol diet by quantitative real-time polymerase chain reaction. Expression of IL-6 and VCAM-1 was significantly reduced in P2Y 6 -deficient atherosclerotic lesions, whereas MCP-1 and ICAM-1 did not differ when compared with respective controls.…”

Section: P2y 6 Deficiency Limits Plaque Inflammationmentioning

confidence: 99%

“…18 Furthermore, P2Y 6 contributes to inflammation of intestinal mucosa promoting IL-8-dependent neutrophil recruitment. 19 Pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid, a synthetic substance blocking several purinergic receptors including P2Y 6 , P2Y 4 , P2Y 11 , and purinergic receptors X (ion channels), reduced atherosclerosis in apolipoprotein E-deficient mice suggesting that purinergic signaling is also relevant during the inflammatory processes propagating atherogenesis. 20 In the light of these data, we hypothesized that P2Y 6 plays an important role in leukocyte recruitment to the vessel wall and that its deletion may limit experimental atherosclerosis.…”

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confidence: 99%

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P2Y ₆ Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice

Stachon

Peikert

Michel

et al. 2014

ATVB

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Objective-Nucleotides such as ATP, ADP, UTP, and UDP serve as proinflammatory danger signals via purinergic receptors on their release to the extracellular space by activated or dying cells. UDP binds to the purinergic receptor Y 6 (P2Y 6 ) and propagates vascular inflammation by inducing the expression of chemokines such as monocyte chemoattractant protein 1, interleukin-8, or its mouse homologsCCL1 (chemokine [C-C motif] ligand 1)/keratinocyte chemokine, CXCL2 (chemokine [C-X-C motif] ligand 2)/macrophage inflammatory protein 2, and CXCL5 (chemokine [C-X-C motif] ligand 5)/LIX, and adhesion molecules such as vascular cell adhesion molecule 1 and intercellular cell adhesion molecule 1. Thus, P2Y 6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Because atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall, we hypothesized a role of P2Y 6 in atherogenesis. Approach and Results-Intraperitoneal stimulation of wild-type mice with UDP induced rolling and adhesion of leukocytes to the vessel wall as assessed by intravital microscopy. This effect was not present in P2Y 6 -deficient mice. Atherosclerotic aortas of low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks expressed significantly more transcripts and protein of P2Y 6 than respective controls. Finally, P2Y 6 −/− /low-density lipoprotein receptor-deficient mice consuming high-cholesterol diet for 16 weeks developed significantly smaller atherosclerotic lesions compared with P2Y 6 +/+ /low-density lipoprotein receptor-deficient mice. Bone marrow transplantation identified a crucial role of P2Y 6 on vascular resident cells, most likely endothelial cells, on leukocyte recruitment and atherogenesis. Atherosclerotic lesions of P2Y 6 -deficient mice contained fewer macrophages and fewer lipids as determined by immunohistochemistry. Mechanistically, RNA expression of vascular cell adhesion molecule 1 and interleukin-6 was decreased in these lesions and P2Y 6 -deficient macrophages took up less modified low-density lipoprotein cholesterol. 16 demonstrated that P2Y 6 promotes host defense by augmenting the expression of monocyte chemoattractant protein 1 (MCP-1) and guiding monocytes to the location of infection. Besides the chemokine-driven recruitment, also a direct chemoattractant activity of the UDP-P2Y 6 R axis has been described 17 for leukocytes. Thus, stimulation of the P2Y 6 R has been implicated with chronic inflammatory diseases. Indeed, selective inhibition or knockdown of P2Y 6 R reduced all cardinal features of experimental acute and chronic allergic asthma in mice. 18 Furthermore, P2Y 6 contributes to inflammation of intestinal mucosa promoting IL-8-dependent neutrophil recruitment. Conclusions-We 19Pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid, a synthetic substance blocking several purinergic receptors including P2Y 6 , P2Y 4 , P2Y 11 , and purinergic receptors X (ion channels), reduced atherosclerosis in...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: 22mentioning

confidence: 92%

Section: P2y 6 Deficiency Limits Plaque Inflammationmentioning

confidence: 99%

mentioning

confidence: 99%

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P2Y ₆ Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice

Stachon

Peikert

Michel

et al. 2014

ATVB

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P2Y6 regulates cytoskeleton reorganization and cell migration of C2C12 myoblasts via ROCK pathway

Wang

Chen

Yuan-fu

et al. 2017

J of Cellular Biochemistry

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Migration of skeletal muscle precursor cells is required for limb muscle development and skeletal muscle repair. This study aimed to examine the role of P2Y6 receptor in C2C12 myoblasts migration. C2C12 myoblasts were treated with P2Y6 agonist UDP, P2Y6 antagonist MRS2578, Ca channel blocker BTP2, or ROCK inhibitor GSK269962 or Y27632, and the migration ability of C2C12 cells was assessed by wound healing assay. The cellular Ca content was analyzed with fluo-4 probe and the activation of ROCK (phosphorlyation of LIMK and cofilin) was assayed by western blot. The cytoskeleton was labeled with Actin-Tracker Green and Tubulin-Tracker-Red. Silencing P2Y6 expression in C2C12 myoblasts reduced intracellular Ca content and cell motility. Whereas UDP increased cellular Ca content, actin filaments, and cell migration, MRS2578 had the opposite effects. The effects of UDP were abrogated by BTP2 and GSK269962 (and Y27632). Disruption of P2Y6 signaling pathway caused C2C12 myoblasts to have an elongated morphology. These results demonstrated that P2Y6 signaled through Ca influx and RhoA/ROCK to reorganize cytoskeleton and promote migration in myoblasts.

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P2Y₂ receptor promotes intestinal microtubule stabilization and mucosal re‐epithelization in experimental colitis

Degagné

Degrandmaison

Grbic

et al. 2012

Journal Cellular Physiology

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P2Y(2) receptor expression is increased in intestinal epithelial cells (IECs) during inflammatory bowel diseases (IBDs). In this context, P2Y(2) stimulates PGE(2) release by IECs, suggesting a role in wound healing. For this study, we have used the non-cancerous IEC-6 cell line. IEC-6 cell migration was determined using Boyden chambers and the single-edged razor blade model of wounding. The receptor was activated using ATP, UTP, or 2-thioUTP. Pharmacological inhibitors, a blocking peptide, a neutralizing antibody and interfering RNAs were used to characterize the signaling events. Focal adhesions and microtubule (MT) dynamics were determined by immunofluorescence using anti-vinculin and anti-acetylated-α-tubulin antibodies, respectively. In vivo, the dextran sodium sulfate mouse model of colitis was used to characterize the effects of P2Y(2) agonist 2-thioUTP on remission. We showed that P2Y(2) increased cell migration and wound closure by recruiting Go protein with the cooperation of integrin α(v) . Following P2Y(2) activation, we demonstrated that GSK3β activity was inhibited in response to Akt activation. This leads to MT stabilization and increased number of focal adhesions. In vivo, P2Y(2) activation stimulates remission, as illustrated by a reduction in the disease activity index values and histological scores as compared to control mice. These findings highlight a novel function for this receptor in IECs. They also illustrate that P2Y receptors could be targeted for the development of innovative therapies for the treatment of IBDs.

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P2Y6 Receptor Contributes to Neutrophil Recruitment to Inflamed Intestinal Mucosa by Increasing Cxc Chemokine Ligand 8 Expression in an AP-1-dependent Manner in Epithelial Cells

Abstract: This study not only describes the P2Y(6) signaling mechanism regulating CXCL8 expression in IEC, but it also illustrates the potential of targeting P2Y(6) to reduce intestinal inflammation.

Cited by 48 publications

References 59 publications

P2Y ₆ Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice

P2Y ₆ Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice

P2Y6 regulates cytoskeleton reorganization and cell migration of C2C12 myoblasts via ROCK pathway

P2Y₂ receptor promotes intestinal microtubule stabilization and mucosal re‐epithelization in experimental colitis

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P2Y6 Receptor Contributes to Neutrophil Recruitment to Inflamed Intestinal Mucosa by Increasing Cxc Chemokine Ligand 8 Expression in an AP-1-dependent Manner in Epithelial Cells

Abstract: This study not only describes the P2Y(6) signaling mechanism regulating CXCL8 expression in IEC, but it also illustrates the potential of targeting P2Y(6) to reduce intestinal inflammation.

Cited by 48 publications

References 59 publications

P2Y 6 Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice

P2Y 6 Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice

P2Y6 regulates cytoskeleton reorganization and cell migration of C2C12 myoblasts via ROCK pathway

P2Y2 receptor promotes intestinal microtubule stabilization and mucosal re‐epithelization in experimental colitis

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Product

Resources

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P2Y ₆ Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice

P2Y ₆ Deficiency Limits Vascular Inflammation and Atherosclerosis in Mice

P2Y₂ receptor promotes intestinal microtubule stabilization and mucosal re‐epithelization in experimental colitis