NMDA receptor modulation of glutamate release in activated neutrophils
| Autor: | David Cain, Ana Gutierrez del Arroyo, Egor A. Turovsky, Simon Lambden, Seth G. N. Grant, Vitaly Kasymov, Gareth L. Ackland, Jenifer Sanchez, Alexander V. Gourine, Thomas D. Nightingale, Anna Hadjihambi |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Research paper Neutrophils Glutamic Acid Inflammation Apoptosis Receptors N-Methyl-D-Aspartate General Biochemistry Genetics and Molecular Biology Neutrophil Activation Serine 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Cell Line Tumor medicine Animals Humans Glutamate Neutrophils N-Methylaspartate Neuroinflammation Systemic Receptor Neurons Glutamate receptor General Medicine Xenograft Model Antitumor Assays 3. Good health Respiratory burst Cell biology Disease Models Animal 030104 developmental biology chemistry nervous system 030220 oncology & carcinogenesis Phorbol NMDA receptor Calcium medicine.symptom Reactive Oxygen Species Postsynaptic density Biomarkers |
| Zdroj: | Del Arroyo, A G, Hadjihambi, A, Sanchez, J, Turovsky, E, Kasymov, V, Cain, D, Nightingale, T D, Lambden, S, Grant, S G N, Gourine, A V & Ackland, G L 2019, ' NMDA receptor modulation of glutamate release in activated neutrophils ', EBioMedicine . https://doi.org/10.1016/j.ebiom.2019.08.004 EBioMedicine |
| DOI: | 10.1016/j.ebiom.2019.08.004 |
| Popis: | Background Neutrophil depletion improves neurologic outcomes in experimental sepsis/brain injury. We hypothesized that neutrophils may exacerbate neuronal injury through the release of neurotoxic quantities of the neurotransmitter glutamate. Methods Real-time glutamate release by primary human neutrophils was determined using enzymatic biosensors. Bacterial and direct protein-kinase C (Phorbol 12-myristate 13-acetate; PMA) activation of neutrophils in human whole blood, isolated neutrophils or human cell lines were compared in the presence/absence of N-Methyl-d-aspartic acid receptor (NMDAR) antagonists. Bacterial and direct activation of neutrophils from wild-type and transgenic murine neutrophils deficient in NMDAR-scaffolding proteins were compared using flow cytometry (phagocytosis, reactive oxygen species (ROS) generation) and real-time respirometry (oxygen consumption). Findings Both glutamate and the NMDAR co-agonist d-serine are rapidly released by neutrophils in response to bacterial and PMA-induced activation. Pharmacological NMDAR blockade reduced both the autocrine release of glutamate, d-serine and the respiratory burst by activated primary human neutrophils. A highly specific small-molecule inhibitor ZL006 that limits NMDAR-mediated neuronal injury also reduced ROS by activated neutrophils in a murine model of peritonitis, via uncoupling of the NMDAR GluN2B subunit from its' scaffolding protein, postsynaptic density protein-95 (PSD-95). Genetic ablation of PSD-95 reduced ROS production by activated murine neutrophils. Pharmacological blockade of the NMDAR GluN2B subunit reduced primary human neutrophil activation induced by Pseudomonas fluorescens, a glutamate-secreting Gram-negative bacillus closely related to pathogens that cause hospital-acquired infections. Interpretation These data suggest that release of glutamate by activated neutrophils augments ROS production in an autocrine manner via actions on NMDAR expressed by these cells. Fund GLA: Academy Medical Sciences/Health Foundation Clinician Scientist. AVG is a Wellcome Trust Senior Research Fellow. Graphical abstract Unlabelled Image Highlights • Neutrophil depletion improves neurologic outcome after injury and infection. • Pharmacologic NMDAR blockade reduces rapid autocrine release of glutamate/d-serine from activated neutrophils. • Genetic ablation/small-molecule inhibition of PSD-95 reduces neutrophil ROS. • NMDAR blockade reduces human neutrophil activated by glutamate-secreting bacteria. • Activated neutrophils may exacerbate neuronal injury in various forms of critical illness through the release of glutamate. |
| Databáze: | OpenAIRE |
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