Roles of the tissue-type plasminogen activator in immune response

Seillier, Célia; Hélie, Pauline; Petit, Gautier; Vivien, Denis; Clemente, Diego; Docagne, Fabián; Toutirais, Olivier

doi:10.1016/j.cellimm.2021.104451

Cited by 22 publications

(10 citation statements)

References 83 publications

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“…Through this interaction, tPA, an important component of the pathophysiology of many neurovascular and neurodegenerative disorders [ 101 , 107 , 217 ], promotes NMDAR over-activation and subsequent toxicity on the BBB and neurons [ 46 ]. In inflammatory conditions, the presence of tPA potentiates vascular endothelial NMDAR activity close to the tight-junctions and the Rho/ROCK pathway leading to an increase in BBB permeability leading to the infiltration of immune cells into the brain [ 111 , 112 , 114 , 119 ]. Glunomab is counteracting both the neuroinflammation directly linked to the increase of the permeability of the BBB and the following transmigration of toxic inflammatory cells into the brain parenchyma and the associated excitotoxicity mechanisms on neuronal synapses.…”

Section: Discussionmentioning

confidence: 99%

“…Zhu and collaborators showed that GluN1 ATD is highly mobile and actively participates in defining the gating and pharmacological profile of NMDARs, suggesting that any ligand binding on GluN1 ATD may stabilize its opened or closed conformations [ 340 ]. Among these ATD-GluN1-NMDARs modulators, the extracellular serine protease tPA, expressed by neurons and other cell types such as vascular endothelial cells [ 109 , 116 ], has been reported to have pleiotropic functions through the CNS and vascular structure [ 112 , 114 , 341 , 342 , 343 ]. By interacting with GluN1, tPA promotes an over-activation of NMDARs inducing neuronal death dependently or independently of its proteolytic activity [ 45 , 338 ].…”

Section: Modulators Of Nmdars For the Treatment Of Neurological Disor...mentioning

confidence: 99%

“…On vascular endothelial cells, this innovative antibody restores the BBB integrity preventing the Rho/ROCK signaling activation and blocking the transmigration of inflammatory cells and the associated neuroinflammation processes without modifying the T cell activation [ 107 , 112 ]. On neurons, Glunomab prevents the excitotoxic effects of tPA and also interferes with the diffusion of NMDARs outside the synapse by blocking the translocation of NMDARs from the synaptic to the extra-synaptic compartment, an important hallmark described in psychotic diseases such as SCZ and anti-NMDAR encephalitis [ 46 , 258 ].…”

Section: Modulators Of Nmdars For the Treatment Of Neurological Disor...mentioning

confidence: 99%

“…In the vascular compartment, NMDARs are expressed at the luminal surface of the endothelial cells and close to the tight junctions [ 109 , 110 ]. Endothelial NMDARs (eNMDARs) are likely important regulators of blood-brain and blood-spinal cord barriers maintenance and permeability, oxidative stress, neurovascular inflammatory processes, immune cell transmigration, mitochondrial function, nitric oxide (NO) generation and are part of the neurovascular unit (NVU) [ 108 , 111 , 112 , 113 , 114 ]. The NVU is considered the smallest signaling module in the brain that, besides neurons and microvascular endothelial cells, encompasses mural cells as pericytes, astrocytes, and/or smooth muscle cells, depending on the cerebrovascular tree position [ 115 ].…”

Section: Introductionmentioning

confidence: 99%

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Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

Seillier

Lesept

Toutirais

et al. 2022

IJMS

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The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research. The diversity of NMDAR subtypes and their signaling pathways give rise to pleiotropic functions such as brain development, neuronal plasticity, maturation along with excitotoxicity, blood-brain barrier integrity, and inflammation. NMDARs have thus emerged as key targets for the treatment of neurological disorders. By their large extracellular regions and complex intracellular structures, NMDARs are modulated by a variety of endogenous and pharmacological compounds. Here, we will present an overview of NMDAR functions on neurons and other important cell types involved in the pathophysiology of neurodegenerative, neurovascular, mental, autoimmune, and neurodevelopmental diseases. We will then discuss past and future development of NMDAR targeting drugs, including innovative and promising new approaches.

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Section: Discussionmentioning

confidence: 99%

Section: Modulators Of Nmdars For the Treatment Of Neurological Disor...mentioning

confidence: 99%

Section: Modulators Of Nmdars For the Treatment Of Neurological Disor...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

Seillier

Lesept

Toutirais

et al. 2022

IJMS

Self Cite

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“…Plasmin is activated through the conversion of the proenzyme plasminogen by the enzymatic cleavage of 19-amino acid polypeptides catalyzed by the tissue type plasminogen activator (tPA) or urokinase plasminogen activator (uPA) . The regulation of fibrinolytic activity of plasmin plays roles in cell migration, wound healing, tissue remodeling, tumor therapy, immune response, and inflammation . Recent studies indicate that the regulation of fibrinolytic pathways may also offer a promising therapeutic target for the 2019 coronavirus (COVID-19) disease .…”

Section: Introductionmentioning

confidence: 99%

Cysteine-Derived Chiral Carbon Quantum Dots: A Fibrinolytic Activity Regulator for Plasmin to Target the Human Islet Amyloid Polypeptide for Type 2 Diabetes Mellitus

Yang

Wang

et al. 2023

ACS Appl. Mater. Interfaces

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The fibrillization and deposition of the human islet amyloid polypeptide (hIAPP) are the pathological hallmark of type 2 diabetes mellitus (T2DM), and these insoluble fibrotic depositions of hIAPP are considered to strongly affect insulin secretion by inducing toxicity toward pancreatic islet β-cells. The current strategy of preventing amyloid aggregation by nanoparticle-assisted inhibitors can only disassemble fibrotic amyloids into more toxic oligomers and/or protofibrils. Herein, for the first time, we propose a type of cysteine-derived chiral carbon quantum dot (CQD) that targets plasmin, a core natural fibrinolytic protease in humans. These CQDs can serve as fibrinolytic activity regulators for plasmin to cleave hIAPP into nontoxic polypeptides or into even smaller amino acid fragments, thus alleviating hIAPP's fibrotic amyloid-induced cytotoxicity.Our experiments indicate that chiral CQDs have opposing effects on plasmin activity. The L-CQDs promote the cleavage of hIAPP by enhancing plasmin activity at a promotion ratio of 23.2%, thus protecting β-cells from amyloid-induced toxicity. In contrast, the resultant D-CQDs significantly inhibit proteolysis, decreasing plasmin activity by 31.5% under the same reaction conditions. Second harmonic generation (SHG) microscopic imaging is initially used to dynamically characterize hIAPP before and after proteolysis. The L-CQD promotion of plasmin activity thus provides a promising avenue for the hIAPP-targeted treatment of T2DM to treat low fibrinolytic activity, while the D-CQDs, as inhibitors of plasmin activity, may improve patient survival for hyperfibrinolytic conditions, such as those existing during surgeries and traumas.

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UV‐Triggered Hydrogel Coating of the Double Network Polyelectrolytes for Enhanced Endothelialization

Wang,

Yin,

Wang

et al. 2024

Advanced Science

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The left atrial appendage (LAA) occluder is an important medical device for closing the LAA and preventing stroke. The device‐related thrombus (DRT) prevents the implantation of the occluder in exerting the desired therapeutic effect, which is primarily caused by the delayed endothelialization of the occluder. Functional coatings are an effective strategy for accelerating the endothelialization of occluders. However, the occluder surface area is particularly large and structurally complex, and the device is subjected to a large shear friction in the sheath during implantation, which poses a significant challenge to the coating. Herein, a hydrogel coating by the in situ UV‐triggered polymerization of double‐network polyelectrolytes is reported. The findings reveal that the double network and electrostatic interactions between the networks resulted in excellent mechanical properties of the hydrogel coating. The sulfonate and Arg‐Gly‐Asp (RGD) groups in the coating promoted hemocompatibility and endothelial growth of the occluder, respectively. The coating significantly accelerated the endothelialization of the LAA occluder in a canine model is further demonstrated. This study has potential clinical benefits in reducing both the incidence of DRT and the postoperative anticoagulant course for LAA closure.

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Roles of the tissue-type plasminogen activator in immune response

Cited by 22 publications

References 83 publications

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases

Cysteine-Derived Chiral Carbon Quantum Dots: A Fibrinolytic Activity Regulator for Plasmin to Target the Human Islet Amyloid Polypeptide for Type 2 Diabetes Mellitus

UV‐Triggered Hydrogel Coating of the Double Network Polyelectrolytes for Enhanced Endothelialization

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