Exacerbated intestinal inflammation in P2Y6 deficient mice is associated with Th17 activation

Salem, Mabrouka; Azreq, Mohammed Amine El; Pelletier, Julien; Robaye, Bernard; Aoudjit, Fawzi; Sévigny, Jean

doi:10.1016/j.bbadis.2019.06.019

Cited by 29 publications

(20 citation statements)

References 68 publications

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“…P2 purinergic receptors are involved in a series of crucial physiological functions [42]. The relationship between P2Y 6 receptor and inflammation has been extensively explored and is controversial [43][44][45][46][47][48][49]. In most cases, activation of the P2Y 6 receptor would promote inflammatory response in macrophages [43][44][45].…”

Section: Discussionmentioning

confidence: 99%

“…Beyond that, the P2Y 6 receptor is widely expressed on the cell surface of intimal endothelial cells [14,50], medial VSMCs [50,51], macrophages or T cells [52][53][54], and perivascular adipocytes [55], which all take part in AAA formation. There are still evidences demonstrating that activation of P2Y 6 could exert an anti-inflammation role in different kinds of cells [46,47], such as T cells. For example, Salem et al [46] found that P2Y 6 receptor -/mice exacerbated intestinal inflammation induced by dextran sulfate sodium partly via increased recruitment of Th17/Th1 lymphocytes, whose infiltration contributes to formation of AAA [53,54].…”

Section: Discussionmentioning

confidence: 99%

“…There are still evidences demonstrating that activation of P2Y 6 could exert an anti-inflammation role in different kinds of cells [46,47], such as T cells. For example, Salem et al [46] found that P2Y 6 receptor -/mice exacerbated intestinal inflammation induced by dextran sulfate sodium partly via increased recruitment of Th17/Th1 lymphocytes, whose infiltration contributes to formation of AAA [53,54]. In another study, the specific absence of the P2Y 6 receptor on T cells amplified cytokine generation, T cell activation, and subsequently exuberant allergen-induced pulmonary inflammation [47].…”

Section: Discussionmentioning

confidence: 99%

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The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II‐Induced Abdominal Aortic Aneurysms

Zhang

Xiang

et al. 2020

BioMed Research International

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Objective. The P2Y 6 receptor has been shown to be involved in many cardiovascular diseases, including hypertension and atherosclerosis. The study is aimed at exploring the role of the P2Y 6 receptor in Ang II-induced abdominal aortic aneurysm (AAA) formation in apolipoprotein E-deficient (apoE -/-) mice by using its selective antagonist. Methods. Male apoE -/mice were fed with high-fat diet and infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Mice were divided into four groups: normal saline (NS, placebo control) group (n = 8), Ang II+vehicle (Ang II) group (n = 14), Ang II-low dose MRS2578 (Ang II+MRS-16 mg) group (n = 14), and Ang II-high dose MRS2578 (Ang II+MRS-32 mg) group (n = 14). Daily intraperitoneal injection with vehicle or MRS2578 was pretreated one week before Ang II infusion. On postoperative day 10, aorta imaging of each group was taken by ultrasonography. After 4 weeks of Ang II infusion, the excised aortas were processed for diameter measurement and quantification of aneurysm severity and tissue characteristics; the blood samples were collected for measurement of the lipid profile and levels of cytokines. Verhoeff's Van Gieson (EVG) staining and immunochemistry staining were performed to evaluate disruption of the extracellular matrix (ECM) and infiltration of macrophages. Expression and activity of matrix metalloproteinases (MMPs) was measured by gelatin zymography. Results. Treatment with MRS2578 made no significant difference in AAA formation, and maximal aortic diameter yet caused higher AAA rupture-induced mortality from 7% (Ang II) to 21.4% (Ang II+MRS-16 mg) or 42.9% (Ang II+MRS-32 mg), respectively (p < 0:05). Consistently, the severity of aneurysm tended to be more deteriorated in MRS2578-treated groups, especially the high-dosage group. The ratios of type III and IV aneurysm were much higher in the MRS2578-coadministered groups (p < 0:05). Furthermore, histological analyses showed that administration of MRS2578 significantly increased infiltration of macrophages, expression of monocyte chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1), and activities of MMP-2 and MMP-9 followed by aggravating degradation elastin in vivo (p < 0:05). However, the multiple effects of MRS2578 on the development of AAA are independent of changes in systolic blood pressure and lipid profiles. Conclusions. The present study demonstrated that administration of MRS2578 exacerbated the progression and rupture of experimental AAA through promoting proinflammatory response and MMP expression and activity, which indicated a crucial role of the P2Y 6 receptor in AAA development. Clinical Relevance. Purinergic P2Y receptors have attracted much attention since the P2Y 12 receptor antagonist had been successfully applied in clinical practice. Elucidating the underlying mechanisms of AAA and exploring potential therapeutic strategies are essential to prevent its progression and reduce the mortality rate.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II‐Induced Abdominal Aortic Aneurysms

Zhang

Xiang

et al. 2020

BioMed Research International

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“…Although the P2Y 6 receptor clearly has pro-inflammatory potential, it may also have protective effects. P2Y 6 receptor-deficient mice were more susceptible to inflammation in the dextran sodium sulfate (DSS) murine model of inflammatory bowel disease (IBD) [ 75 ]. The P2Y 6 receptor appears to prevent the development of IBD at least in part via blockade of T helper 17 (Th17) cells.…”

Section: P2y 6 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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“…Another study identified a specific activity of P2Y6R that was found to regulate CXCL8 expression in IEC, promoting neutrophil recruitment and inflammatory responses (35). In contrast, in murine models of DSS colitis, P2Y6R deletion has been associated with extensive intestinal inflammation, resulting from increased recruitment of Th17/Th1 lymphocytes in the gut mucosa (36).…”

Section: P2y Receptorsmentioning

confidence: 99%

Control of Gut Inflammation by Modulation of Purinergic Signaling

et al. 2020

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Inflammatory bowel disease (IBD) is a serious inflammatory condition of the gastrointestinal tract. Crohn's disease (CD) and ulcerative colitis (UC) are two of the most common IBD manifestations and are both associated with unfettered inflammation, often refractory to conventional immunosuppressive treatment. In both conditions, imbalance between effector and regulatory cell immune responses has been documented and is thought to contribute to disease pathogenesis. Purinergic signaling is a known modulator of systemic and local inflammation and growing evidences point to extracellular ATP/adenosine imbalance as a key determinant factor in IBD-associated immune dysregulation. In vitro and pre-clinical studies suggest a role for both ATP (P2) and adenosine (P1) receptors in dictating onset and severity of the disease. Moreover, our experimental data indicate ENTPD1/CD39 and CD73 ectoenzymes as pivotal modulators of intestinal inflammation, with clear translational importance. Here we will provide an updated overview of the current knowledge on the role of the purinergic signaling in modulating immune responses in IBD. We will also review and discuss the most promising findings supporting the use of purinergic-based therapies to correct immune dysregulation in CD and UC.

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Exacerbated intestinal inflammation in P2Y6 deficient mice is associated with Th17 activation

Cited by 29 publications

References 68 publications

The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II‐Induced Abdominal Aortic Aneurysms

The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II‐Induced Abdominal Aortic Aneurysms

Control of Macrophage Inflammation by P2Y Purinergic Receptors

Control of Gut Inflammation by Modulation of Purinergic Signaling

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Exacerbated intestinal inflammation in P2Y6 deficient mice is associated with Th17 activation

Cited by 29 publications

References 68 publications

The Role of a Selective P2Y6 Receptor Antagonist, MRS2578, on the Formation of Angiotensin II‐Induced Abdominal Aortic Aneurysms

The Role of a Selective P2Y6 Receptor Antagonist, MRS2578, on the Formation of Angiotensin II‐Induced Abdominal Aortic Aneurysms

Control of Macrophage Inflammation by P2Y Purinergic Receptors

Control of Gut Inflammation by Modulation of Purinergic Signaling

Contact Info

Product

Resources

About

The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II‐Induced Abdominal Aortic Aneurysms

The Role of a Selective P2Y₆ Receptor Antagonist, MRS2578, on the Formation of Angiotensin II‐Induced Abdominal Aortic Aneurysms