ADP exerts P2Y12 -dependent and P2Y12 -independent effects on primary human T cell responses to stimulation

Vemulapalli, Harika; Albayati, Samara; Patwa, Viren; Tilley, Douglas G.; Tsygankov, Alexander Y.; Liverani, Elisabetta

doi:10.1007/s12079-019-00540-8

Cited by 11 publications

(22 citation statements)

References 53 publications

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“…Indeed, P2Y 12 receptor blockage influences T cell activation and cell proliferation. The effect of ADP is specific for CD4 and CD8 T cells, while P2Y 12 antagonism alters these effects, suggesting functional expression of P2Y 12 on T cells (Vemulapalli et al, 2019). We showed previously that silica-induced inflammation increased macrophage, neutrophil, dendritic cell, as well as lymphocyte infiltration (CD4 + and CD8 + ) in lung parenchyma (Moncao-Ribeiro et al, 2014).…”

Section: Discussionmentioning

confidence: 73%

“…Purinergic signaling participates in IL-1β secretion by macrophages, as well as in NO production through P2X7 activation, as previously demonstrated by our group. On the other hand, P2Y 12 receptor does not participate in cytokine secretion (Vemulapalli et al, 2019), but its blockage significantly reduced NO and the pro-inflammatory mediators IL-6 and TNFα, due to reduced cellular recruitment.…”

Section: Discussionmentioning

confidence: 92%

“…More recently, P2Y 12 expression has been described also in immune cells, such as monocytes (Micklewright et al, 2018), dendritic cells (Ben Addi et al, 2010), and T lymphocytes (Wang et al, 2004). Furthermore, blocking P2Y 12 pathways alters T cell activation and changes the cell population (Vemulapalli et al, 2019). In the respiratory system, P2Y 12 receptor appears to contribute to inflammatory response, participating in allergic and non-allergic processes (Paruchuri et al, 2009;Shirasaki et al, 2013;Suh et al, 2016), as well as autoimmune disease processes (Domercq et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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P2Y12 Receptor Antagonist Clopidogrel Attenuates Lung Inflammation Triggered by Silica Particles

et al. 2020

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Silicosis is an occupational lung disease caused by inhalation of silica particles. It is characterized by intense lung inflammation, with progressive and irreversible fibrosis, leading to impaired lung function. Purinergic signaling modulates silica-induced lung inflammation and fibrosis through P2X7 receptor. In the present study, we investigate the role of P2Y 12 , the G-protein-coupled subfamily prototype of P2 receptor class in silicosis. To that end, BALB/c mice received an intratracheal injection of PBS or silica particles (20 mg), without or with P2Y 12 receptor blockade by clopidogrel (20 mg/kg body weight by gavage every 48 h) -groups CTRL, SIL, and SIL + Clopi, respectively. After 14 days, lung mechanics were determined by the end-inflation occlusion method. Lung histology was analyzed, and lung parenchyma production of nitric oxide and cytokines (IL-1β, IL-6, TNF-α, and TGF-β) were determined. Silica injection reduced animal survival and increased all lung mechanical parameters in relation to CTRL, followed by diffuse lung parenchyma inflammation, increased neutrophil infiltration, collagen deposition and increased pro-inflammatory and profibrogenic cytokine secretion, as well as increased nitrite production. Clopidogrel treatment prevented silica-induced changes in lung function, and significantly reduced lung inflammation, fibrosis, as well as cytokine and nitrite production. These data suggest that inhibition of P2Y 12 signaling improves silica-induced lung inflammation, preventing lung functional changes and mortality. Our results corroborate previous observations of silica-induced lung changes and expand the understanding of purinergic signaling in this process.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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P2Y12 Receptor Antagonist Clopidogrel Attenuates Lung Inflammation Triggered by Silica Particles

et al. 2020

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“…The P2Y 12 receptor was originally sought to be exclusively expressed on platelets, with about 400 copies of the P2Y 12 receptor per cell, and to a lesser extent in subregions of the brain [11,15]. However, further studies demonstrated that P2Y 12 has a wider tissue distribution, being expressed and functional in microglial cells [16], vascular smooth muscle cells [17,18], and on several immune cells including dendritic cells [19], mast cells [20], eosinophils [21], monocytes [22], lymphocytes [23,24] and macrophages [25]. The P2Y 12 receptor expression has been also recently reported in osteoclasts [26] as well as in brain and breast cancer cell lines [27].…”

Section: Expression Of P2y 12 Receptormentioning

confidence: 99%

“…Micklewright et al demonstrated in human THP-1 monocytic cells that P2Y 12 was expressed and positively regulated P2Y6-mediated intracellular Ca 2+ signaling through suppression of adenylate cyclase activity [22]. Finally, Vemulapalli et al recently showed that functional P2Y 12 was expressed by T lymphocytes and that it exerted effects on biological responses of T cells when stimulated [23].…”

Section: Role Of Non-platelet P2y 12 Receptorsmentioning

confidence: 99%

P2Y12 Inhibition beyond Thrombosis: Effects on Inflammation

Gaussem

Bachelot‐Loza

Nesseler

et al. 2020

IJMS

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The P2Y12 receptor is a key player in platelet activation and a major target for antithrombotic drugs. The beneficial effects of P2Y12 receptor antagonists might, however, not be restricted to the primary and secondary prevention of arterial thrombosis. Indeed, it has been established that platelet activation also has an essential role in inflammation. Additionally, nonplatelet P2Y12 receptors present in immune cells and vascular smooth muscle cells might be effective players in the inflammatory response. This review will investigate the biological and clinical impact of P2Y12 receptor inhibition beyond its platelet-driven antithrombotic effects, focusing on its anti-inflammatory role. We will discuss the potential molecular and cellular mechanisms of P2Y12-mediated inflammation, including cytokine release, platelet–leukocyte interactions and neutrophil extracellular trap formation. Then we will summarize the current evidence on the beneficial effects of P2Y12 antagonists during various clinical inflammatory diseases, especially during sepsis, acute lung injury, asthma, atherosclerosis, and cancer.

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P2Y12 antagonism results in altered interactions between platelets and regulatory T cells during sepsis

Albayati

Vemulapalli

Tsygankov

2020

Journal of Leukocyte Biology

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Sepsis is a complex clinical condition resulting from a serious bloodstream infection. With mortality rates as high as 50%, improved treatments are needed. Regulatory T cells (Tregs), a subset of T lymphocytes, promote the resolution of inflammation. Septic patients have elevated levels of circulating Tregs. Platelets influence the proliferation and activation of Tregs in vitro. However, modulating platelet‐Tregs interaction during sepsis may restraing Treg proliferation, leading to the restoration of immunologic homeostasis. P2Y12 is a purinergic receptor present on platelets and T lymphocytes. Blocking P2Y12 improves the outcome of sepsis. We investigated whether blocking P2Y12 alters platelet–Treg interaction in vivo. We used the murine model of sepsis, cecal ligation, and puncture (CLP) and we blocked P2Y12 using the P2Y12 antagonist, clopidogrel. Twenty‐four hours after surgery, we measured Treg population sizes in the spleens of the Sham, CLP, and CLP + clopidogrel groups. We investigated the effect of blocking P2Y12 in vitro using cocultures of human platelets and T cells with or without anti‐CD3/CD28. P2Y12 was blocked using AR‐C69931MX. Treg population sizes were reduced in the septic mice treated with clopidogrel compared with untreated septic mice. Aggregation of platelets and CD4+ T cells was reduced in treated CLP mice compared with untreated CLP mice. P2Y12 antagonism changes how platelets influence T cells in vitro, depending on T‐cell activation. In conclusion, blockade of the P2Y12 signaling pathway restrains Treg proliferation in vivo and in vitro. Targeting platelets to control Treg proliferation and activity may be a promising strategy for treating sepsis.

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ADP exerts P2Y12 -dependent and P2Y12 -independent effects on primary human T cell responses to stimulation

Cited by 11 publications

References 53 publications

P2Y12 Receptor Antagonist Clopidogrel Attenuates Lung Inflammation Triggered by Silica Particles

P2Y12 Receptor Antagonist Clopidogrel Attenuates Lung Inflammation Triggered by Silica Particles

P2Y12 Inhibition beyond Thrombosis: Effects on Inflammation

P2Y12 antagonism results in altered interactions between platelets and regulatory T cells during sepsis

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