ArticleJournal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism2020
Excitatory pathway engaging glutamate, calcineurin, and NFAT upregulates IL-4 in ischemic neurons to polarize microglia.
Article in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 48 citations in OpenAlex.
- Effect of Anti-Glutamate Antibodies on the Content of IL-4 and IL-10 in Brain Structures in Aged Mice with Induced Memory Impairment.Bulletin of experimental biology and medicine · 2025Article
- Calcineurin inhibition may prevent Alzheimer disease in people with Down syndrome.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Review
- Delta-opioid receptor signaling alleviates neuropathology and cognitive impairment in the mouse model of Alzheimer's disease by regulating microglia homeostasis and inhibiting HMGB1 pathway.Alzheimer's research & therapy · 2025Article
- Early-life IL-4 administration induces long-term changes in microglia in the cerebellum and prefrontal cortex.Journal of neurochemistry · 2025Article
- Cerebrospinal fluid metabolomes of treatment-resistant depression subtypes and ketamine response: a pilot study.Discover mental health · 2024Article
- Long-term normalization of calcineurin activity in model mice rescues Pin1 and attenuates Alzheimer's phenotypes without blocking peripheral T cell IL-2 response.Alzheimer's research & therapy · 2023Article
- Effect of Rosiglitazone, the Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, on Apoptosis, Inflammatory Cytokines and Oxidative Stress in pentylenetetrazole-Induced Seizures in Kindled Mice.Neurochemical research · 2023Article
- Rapamycin Augmentation of Chronic Ketamine as a Novel Treatment for Complex Regional Pain Syndrome.Cureus · 2023Article
- Role of post-ischemic phase-dependent modulation of anti-inflammatory M2-type macrophages against rat brain damage.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2023Article
- Regulation of microglia polarization after cerebral ischemia.Frontiers in cellular neuroscience · 2023Review
- Targeting CaN/NFAT in Alzheimer's brain degeneration.Frontiers in immunology · 2023Review
- Erythropoietin promotes the differentiation of fetal neural stem cells into glial cells via the erythropoietin receptor-β common receptor/Syne-1/H3K9me3 pathway.CNS neuroscience & therapeutics · 2022Article
- Microglial phagocytosis and regulatory mechanisms after stroke.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2022Article
- SerpinA3N attenuates ischemic stroke injury by reducing apoptosis and neuroinflammation.CNS neuroscience & therapeutics · 2022Article
- The promise of exosome applications in treating central nervous system diseases.CNS neuroscience & therapeutics · 2021Review
- Intranasal delivery of interleukin-4 attenuates chronic cognitive deficits via beneficial microglial responses in experimental traumatic brain injury.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2021Article
- Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.Aging cell · 2021Article
- Interleukin-4 improves white matter integrity and functional recovery after murine traumatic brain injury via oligodendroglial PPARγ.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2021Article
- Endogenous Regulatory T Cells Promote M2 Macrophage Phenotype in Diabetic Stroke as Visualized by Optical Imaging.Translational stroke research · 2021Article
- Treadmill Exercise Attenuates Cerebral Ischemia-Reperfusion Injury by Promoting Activation of M2 Microglia via Upregulation of Interleukin-4.Frontiers in cardiovascular medicine · 2021Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Excitotoxicity and microglia/macrophage over-activation are the important pathogenic steps in brain damage caused by ischemic stroke. Recent studies from our group suggest that the neurons in ischemic penumbra generate an anti-inflammatory cytokine, interleukin-4 (IL-4). This neuron-produced IL-4 could subsequently convert surrounding microglia/macrophages to a reparative (M2)-phenotype. The present study was designed to establish the mechanisms by which neurons under transient ischemic condition produce/secrete IL-4. We employed primary rat cortical neurons and a validated in vitro ischemic injury model involving transient oxygen-glucose deprivation (OGD). We discovered that only sublethal OGD induces IL-4 production/secretion by neurons. We then showed that excitotoxic stimulus (an integral component of OGD-mediated damage) involving N-methyl-D-aspartate (NMDA), and not kainate receptor, triggers neuronal IL-4 production/release. Of note, oxidative stress or pro-apoptotic stimuli did not induce IL-4 production by neurons. Next, using the calcineurin inhibitor FK506, we implicated this phosphatase in activation of the nuclear factor of activated T-cells (NFAT; a transcription factor activated through calcineurin-mediated dephosphorylation) and propose that this pathway is involved in transcriptional upregulation of the IL-4 synthesis in NMDA-treated neurons. Finally, using a transfer of culture medium from NMDA-conditioned neuron to microglia, we showed that the neuronal IL-4 can polarize microglia toward a restorative, phagocytic phenotype.
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Registered trials
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