NOD2-mediated P2Y12 upregulation increases platelet activation and thrombosis in sepsis

Zhong, Haoxuan; Waresi, Maieryemu; Zhang, Wei; Han, Liping; Zhao, Yikai; Chen, Yufei; Zhou, Peng; Chang, Lin; Pan, Guanxing; Wu, Bangwei; Li, Jian; Zhang, Si; H, Shi; Luo, Xinping; Gao, Wen; Zhou, Qi; Ding, Zhongren

doi:10.1016/j.bcp.2021.114822

Cited by 10 publications

(15 citation statements)

References 49 publications

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“…127 Upregulation of P 2 Y 12 receptor on the platelet surface and augmented mRNA expression was recently described in patients with acute coronary syndrome, type 2 diabetes mellitus, and sepsis, as associated with platelet hyperreactivity and thrombosis. [128][129][130] The surface expression of PAR1 receptors widely varies among healthy individuals 131 and was shown to increase in various inflammatory conditions, including atherosclerotic cardiovascular disease, arthritis, and asthma. 132,133 Analyzing the surface expression of P 2 Y 12 and PAR1 on platelets under shear, we found that levels of these receptors on resting platelets are rather low; both P2Y12+ and PAR1+ platelet populations further decreased with increasing shear magnitude (Fig.…”

Section: Discussionmentioning

confidence: 99%

Shear-Mediated Platelet Microparticles Demonstrate Phenotypic Heterogeneity as to Morphology, Receptor Distribution, and Hemostatic Function

Roka‐Moiia

Ammann

Miller-Gutierrez

et al. 2023

Preprint

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Objective: Implantable cardiovascular therapeutic devices (CTD) including stents, percutaneous heart valves, and ventricular assist devices, while lifesaving, impart supraphysiologic shear stress to platelets resulting in thrombotic and bleeding device-related coagulopathy. We previously demonstrated that shear-mediated platelet dysfunction is associated with downregulation of platelet GPIb-IX-V and αIIbβ3 receptors via generation of platelet-derived microparticles (PDMPs). Here, we test the hypothesis that shear-generated PDMPs manifest phenotypical heterogeneity of their morphology and surface expression of platelet receptors, and modulate platelet hemostatic function. Approach and Results: Human gel-filtered platelets were exposed to continuous shear stress and sonication. Alterations of platelet morphology were visualized using transmission electron microscopy. Surface expression of platelet receptors and PDMP generation were quantified by flow cytometry. Thrombin generation was quantified spectrophotometrically, and platelet aggregation in plasma was measured by optical aggregometry. We demonstrate that platelet exposure to shear stress promotes notable alterations in platelet morphology and ejection of several distinctive types of PDMPs. Shear-mediated microvesiculation is associated with the differential remodeling of platelet receptors with PDMPs expressing significantly higher levels of both adhesion receptors (αIIbβ3, GPIX, PECAM-1, P-selectin, and PSGL-1) and agonist-evoked receptors (P2Y12 & PAR1). Shear-mediated PDMPs have a bidirectional effect on platelet hemostatic function, promoting thrombin generation and inhibiting platelet aggregation induced by collagen and ADP. Conclusion: Shear-generated PDMPs demonstrate phenotypic heterogeneity as to morphologic features and defined patterns of surface receptor alteration and impose a bidirectional effect on platelet hemostatic function. PDMP heterogeneity suggests that a range of mechanisms are operative in the microvesiculation process, contributing to CTD coagulopathy and posing opportunities for therapeutic manipulation.

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Section: Discussionmentioning

confidence: 99%

Shear-Mediated Platelet Microparticles Demonstrate Phenotypic Heterogeneity as to Morphology, Receptor Distribution, and Hemostatic Function

Roka‐Moiia

Ammann

Miller-Gutierrez

et al. 2023

Preprint

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“…Moreover, platelets from septic patients or mice with CLP-induced sepsis show a stronger expression of P2Y 12 receptors promoted by a NOD2-dependent pathway. Indeed, P2Y 12 overexpression was attenuated in septic NOD2-deficient mice [ 111 ].…”

Section: Platelet Receptors In the Response To Infectionmentioning

confidence: 99%

Blood Platelets in Infection: The Multiple Roles of the Platelet Signalling Machinery

Trivigno

Guidetti

Barbieri

et al. 2023

IJMS

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Platelets are classically recognized for their important role in hemostasis and thrombosis but they are also involved in many other physiological and pathophysiological processes, including infection. Platelets are among the first cells recruited to sites of inflammation and infection and they exert their antimicrobial response actively cooperating with the immune system. This review aims to summarize the current knowledge on platelet receptor interaction with different types of pathogens and the consequent modulations of innate and adaptive immune responses.

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Section: P2y 12 Activation In the Immune System Du...mentioning

confidence: 99%

“…Changes in P2Y 12 levels during sepsis have been investigated by Zhong et al, (2021) [ 144 ]. They have shown that in the animal model of sepsis (cecal ligation and puncture, CLP) as well as in septic patients, P2Y 12 protein levels are increased in platelets [ 144 ]. Interestingly, platelet reactivity appeared to be positively regulated to the P2Y 12 content, suggesting that this could be the possible explanation for why platelets seem to be hyper-activated in sepsis.…”

Section: P2y 12 Activation In the Immune System Du...mentioning

confidence: 99%

The Signaling Pathway of the ADP Receptor P2Y12 in the Immune System: Recent Discoveries and New Challenges

Entsie

Kong

Amoafo

et al. 2023

IJMS

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P2Y12 is a G-protein-coupled receptor that is activated upon ADP binding. Considering its well-established role in platelet activation, blocking P2Y12 has been used as a therapeutic strategy for antiplatelet aggregation in cardiovascular disease patients. However, receptor studies have shown that P2Y12 is functionally expressed not only in platelets and the microglia but also in other cells of the immune system, such as in monocytes, dendritic cells, and T lymphocytes. As a result, studies were carried out investigating whether therapies targeting P2Y12 could also ameliorate inflammatory conditions, such as sepsis, rheumatoid arthritis, neuroinflammation, cancer, COVID-19, atherosclerosis, and diabetes-associated inflammation in animal models and human subjects. This review reports what is known about the expression of P2Y12 in the cells of the immune system and the effect of P2Y12 activation and/or inhibition in inflammatory conditions. Lastly, we will discuss the major problems and challenges in studying this receptor and provide insights on how they can be overcome.

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NOD2-mediated P2Y12 upregulation increases platelet activation and thrombosis in sepsis

Cited by 10 publications

References 49 publications

Shear-Mediated Platelet Microparticles Demonstrate Phenotypic Heterogeneity as to Morphology, Receptor Distribution, and Hemostatic Function

Shear-Mediated Platelet Microparticles Demonstrate Phenotypic Heterogeneity as to Morphology, Receptor Distribution, and Hemostatic Function

Blood Platelets in Infection: The Multiple Roles of the Platelet Signalling Machinery

The Signaling Pathway of the ADP Receptor P2Y12 in the Immune System: Recent Discoveries and New Challenges

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