Protease‐activated receptors: An illustrated review

Xu, Han; Nieman, Marvin T.; Kerlin, Bryce A.

doi:10.1002/rth2.12454

Cited by 38 publications

(22 citation statements)

References 31 publications

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“…Protease-activated receptors (PARs) comprise a family of four G protein-coupled receptors (PAR1-PAR4) that are activated by the serine proteases derived from the coagulation cascade, including factor (F) Xa and thrombin (FIIa), immune cells, and pathogens (Willis Fox and Preston, 2020;Han et al, 2021). Protease-activated receptors are considered as nonclassical pattern-recognition receptors (Friebel et al, 2021).…”

Section: Protease Activated Receptor 1/4mentioning

confidence: 99%

Research Progress on the Role of Microglia Membrane Proteins or Receptors in Neuroinflammation and Degeneration

Zhao

Ren

et al. 2022

Front. Cell. Neurosci.

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Microglia are intrinsic immune cells of the central nervous system and play a dual role (pro-inflammatory and anti-inflammatory) in the homeostasis of the nervous system. Neuroinflammation mediated by microglia serves as an important stage of ischemic hypoxic brain injury, cerebral hemorrhage disease, neurodegeneration and neurotumor of the nervous system and is present through the whole course of these diseases. Microglial membrane protein or receptor is the basis of mediating microglia to play the inflammatory role and they have been found to be upregulated by recognizing associated ligands or sensing changes in the nervous system microenvironment. They can then allosterically activate the downstream signal transduction and produce a series of complex cascade reactions that can activate microglia, promote microglia chemotactic migration and stimulate the release of proinflammatory factor such as TNF-α, IL-β to effectively damage the nervous system and cause apoptosis of neurons. In this paper, several representative membrane proteins or receptors present on the surface of microglia are systematically reviewed and information about their structures, functions and specific roles in one or more neurological diseases. And on this basis, some prospects for the treatment of novel coronavirus neurological complications are presented.

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Section: Protease Activated Receptor 1/4mentioning

confidence: 99%

Research Progress on the Role of Microglia Membrane Proteins or Receptors in Neuroinflammation and Degeneration

Zhao

Ren

et al. 2022

Front. Cell. Neurosci.

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“…The thrombin promotes platelet activation by the cleavage of the NH2-terminal domain of PAR-1 and PAR-4. Activated PAR-1 stimulates RhoA activation though ERK1/2 kinases [ 32 , 35 , 36 ], inhibits the accumulation of cAMP, activates phospholipase C, and promotes Ca2+ mobilisation [ 37 , 38 ]. Moreover, PAR-1 activation influences endothelial barrier permeability due to the stimulation of the MAPKs cascade [ 39 ].…”

Section: From Platelet Fibrinogen Receptors To Thrombin Generation: the “Circulating Wound” Modelmentioning

confidence: 99%

Platelets Contribution to Thrombin Generation in Philadelphia-Negative Myeloproliferative Neoplasms: The “Circulating Wound” Model

Lucchesi

Napolitano

Bochicchio

et al. 2021

IJMS

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Current cytoreductive and antithrombotic strategies in MPNs are mostly based on cell counts and on patient’s demographic and clinical history. Despite the numerous studies conducted on platelet function and on the role of plasma factors, an accurate and reliable method to dynamically quantify the hypercoagulability states of these conditions is not yet part of clinical practice. Starting from our experience, and after having sifted through the literature, we propose an in-depth narrative report on the contribution of the clonal platelets of MPNs—rich in tissue factor (TF)—in promoting a perpetual procoagulant mechanism. The whole process results in an unbalanced generation of thrombin and is self-maintained by Protease Activated Receptors (PARs). We chose to define this model as a “circulating wound”, as it indisputably links the coagulation, inflammation, and fibrotic progression of the disease, in analogy with what happens in some solid tumours. The platelet contribution to thrombin generation results in triggering a vicious circle supported by the PARs/TGF-beta axis. PAR antagonists could therefore be a good option for target therapy, both to contain the risk of vascular events and to slow the progression of the disease towards end-stage forms. Both the new and old strategies, however, will require tools capable of measuring procoagulant or prohaemorrhagic states in a more extensive and dynamic way to favour a less empirical management of MPNs and their potential clinical complications.

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“…PAR4 on mice platelets is activated by thrombin in high concentrations and also through interaction with PAR3 in low concentrations [ 23 , 24 ]. PAR4 is present on platelets, endothelial cells [ 25 ], smooth muscle cells [ 26 ], and leukocytes, including T cells [ 27 ] and Tregs [ 28 ]. There seems to be a considerable similarity in the expression of PAR4 in humans and mice [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Platelets differentially modulate CD4+ Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways

et al. 2021

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CD4+FoxP3+ regulatory T cells (CD4+ Tregs) are known to dampen inflammation following severe trauma. Platelets were shown to augment their posttraumatic activation in burn injury, but the exact mechanisms remain unclear. We hypothesized that platelet activation mechanisms via GPIIb/IIIa, fibrinogen, and PAR4 have an immunological effect and modulate CD4+ Treg activation early after trauma. Therefore, C57Bl/6 N mice were injected with tirofiban (GPIIb/IIIa inhibition), ancrod (fibrinogen splitting enzyme), or tcY-NH2 (selective PAR4 antagonist peptide) before inducing a third-degree burn injury of 25% of the total body surface area. Changes in coagulation, and local and systemic CD4+ Treg activity were assessed via rotational thromboelastometry (ROTEM®) and phospho-flow cytometry 1 h post intervention. The inhibition of GPIIb/IIIa and fibrinogen locally led to a higher basic activity of CD4+ Tregs compared to non-inhibited animals. In contrast, PAR4 disruption on platelets locally led to an increased posttraumatic activation of CD4+ Tregs. Fibrinogen led to complete elimination of coagulation, whereas GPIIb/IIIa or PAR4 inhibition did not. GPIIb/IIIa receptor and fibrinogen inhibition increase CD4+ Tregs activity independently of trauma. Both are crucial for thrombus formation. We suggest platelets trapped in thrombi are unable to interact with CD4+ Tregs but augment their activity when circulating freely. In contrast, PAR4 seems to reduce CD4+ Treg activation following trauma. In summary, GPIIb/IIIa-, PAR4-, and fibrinogen-dependent pathways in platelets modulate CD4+ Treg baseline activity, independently from their hemostatic functionality. PAR4-dependent pathways modulate the posttraumatic interplay of platelets and CD4+ Tregs.

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Protease‐activated receptors: An illustrated review

Cited by 38 publications

References 31 publications

Research Progress on the Role of Microglia Membrane Proteins or Receptors in Neuroinflammation and Degeneration

Research Progress on the Role of Microglia Membrane Proteins or Receptors in Neuroinflammation and Degeneration

Platelets Contribution to Thrombin Generation in Philadelphia-Negative Myeloproliferative Neoplasms: The “Circulating Wound” Model

Platelets differentially modulate CD4+ Treg activation via GPIIa/IIIb-, fibrinogen-, and PAR4-dependent pathways

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