Excitatory pathway engaging glutamate, calcineurin, and NFAT upregulates IL-4 in ischemic neurons to polarize microglia

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.

Melatonin is an effective protector of gingival cells damaged by the cytotoxic effect of glutamate and DL‐buthionine sulfoximine

“…On the other hand, GLUT is an abundant aminoacidic excitatory neurotransmitter in the brain. 24 There are few reports about its presence and influence on periodontal tissues and in PD. 25 However, GLUT is industrially used as a flavor enhancer in the form of monosodium glutamate.…”

Rosiglitazone polarizes microglia and protects against pilocarpine‐induced status epilepticus

“…Microglia are known to play a critical role in maintaining brain homeostasis . The polarization of microglia has been suggested to play pivotal roles in several different neurological disorders . The activation of microglia after seizure in the epileptic brain has been investigated in several studies .…”

“…39 The polarization of microglia has been suggested to play pivotal roles in several different neurological disorders. [40][41][42][43][44] The activation of microglia after seizure in the epileptic brain has been investigated in several studies. 37,45,46 Furthermore, the role of activated microglia in epileptogenesis has been determined in both inflammatory and noninflammatory processes.…”

Potential microglia‐based interventions for stroke

“…Due to the disruption of the neuronal cytomembrane, intracellular proteins/enzymes or nuclear DNA/RNA and cellular debris are released. Thereafter, damage‐associated molecular pattern molecules (DAMPs), such as ATP, S100, reactive oxygen species (ROS), and high mobility group box 1 (HMGB1), are released . Pattern recognition receptors expressed on resident microglia and infiltrating immune cells bind to these DAMPs, which initiate aseptic immune responses (produce inflammatory cytokines) in compromised tissue to further influence stroke pathology.…”

“…Thereafter, damage-associated molecular pattern molecules (DAMPs), such as ATP, S100, reactive oxygen species (ROS), and high mobility group box 1 (HMGB1), are released. [56][57][58] Pattern recognition receptors expressed on resident microglia and infiltrating immune cells bind to these DAMPs, which initiate aseptic immune responses (produce inflammatory cytokines) in compromised tissue to further influence stroke pathology. Inhibiting this polarized microglial extension toward the stroke core prevents the expansion of the injury.…”