ArticleEBioMedicine2019
NMDA receptor modulation of glutamate release in activated neutrophils.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 28 citations in OpenAlex.
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- A potential therapeutic target: The role of neutrophils in the central nervous system.Brain, behavior, & immunity - health · 2023Review
- Human neutrophils communicate remotely via calcium-dependent glutamate-induced glutamate release.iScience · 2023Article
- Munc18-1 Contributes to Hippocampal Injury in Septic Rats Through Regulation of Syntanxin1A and Synaptophysin and Glutamate Levels.Neurochemical research · 2023Article
- The NMDA receptor regulates integrin activation, ATP release and arterial thrombosis through store-operated CaFrontiers in cardiovascular medicine · 2023Article
- Neutrophil modulation of behavior and cognition in health and disease: The unexplored role of an innate immune cell.Immunological reviews · 2022Review
- Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.International journal of molecular sciences · 2022Review
- Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential.Frontiers in oncology · 2022Review
- MicroRNA-223 inhibits neutrophil extracellular traps formation through regulating calcium influx and small extracellular vesicles transmission.Scientific reports · 2021Article
- nNOS-mediated protein-protein interactions: promising targets for treating neurological and neuropsychiatric disorders.Journal of biomedical research · 2020Article
- Rickettsial pathogen uses arthropod tryptophan pathway metabolites to evade reactive oxygen species in tick cells.Cellular microbiology · 2020Article
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Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundNeutrophil 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.
methodsReal-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).
findingsBoth 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.
interpretationThese 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.