CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and l-type Ca2+ channels upstream of p38 MAPK

Abstract

BackgroundThe chemokine receptor CXCR4 (CD184) and its natural ligand CXCL12 contribute to many physiological processes, including decisions about cell death and survival in the central nervous system. In addition, CXCR4 is a co-receptor for human immunodeficiency virus (HIV)-1 and mediates the neurotoxicity of the viral envelope protein gp120. However, we previously observed that CXCL12 also causes toxicity in cerebrocortical neurons but the cellular mechanism remained incompletely defined.MethodsPrimary neuronal-glial cerebrocortical cell cultures from rat were exposed to a neurotoxicity-inducing CXCL12 concentration for different times and the activity of the stress-associated mitogen-activated protein kinase p38 (p38 MAPK) was assessed using an in vitro kinase assay. Neurotoxicity of CXCL12 and cellular localization of p38 MAPK was analyzed by immunofluorescence microscopy. Pharmacological inhibition of NMDA-type glutamate receptor-gated ion channels (NMDAR) of l-type Ca2+ channels was employed during 12- and 24-h exposure to neurotoxic amounts of CXCL12 to study the effects on active p38 MAPK and neuronal survival by Western blotting and microscopy, respectively. Neurotoxicity of CXCL12 was also assessed during pharmacological inhibition of p38 MAPK.ResultsHere, we show that a neurotoxic amount of CXCL12 triggers a significant increase of endogenous p38 MAPK activity in cerebrocortical cells. Immunofluorescence and Western blotting experiments with mixed neuronal-glial and neuron-depleted glial cerebrocortical cells revealed that the majority of active/phosphorylated p38 MAPK was located in neurons. Blockade of NMDAR-gated ion channels or l-type Ca2+ channels both abrogated an increase of active p38 MAPK and toxicity of CXCL12 in cerebrocortical neurons. Inhibition of l-type Ca2+ channels with nimodipine kept the active kinase at levels not significantly different from baseline while blocking NMDAR with MK-801 strongly reduced phosphorylated p38 MAPK below baseline. Finally, we confirmed that directly blocking p38 MAPK also abrogated neurotoxicity of CXCL12.ConclusionsOur findings link CXCL12-induced neuronal death to the regulation of NMDAR-gated ion channels and l-type Ca2+ channels upstream of p38 MAPK activation.

Neutralization of IL‐17 rescues amyloid‐β‐induced neuroinflammation and memory impairment

“…While CXCL12 is constitutively expressed in the CNS, its role during neuroinflammation still remains unclear. Several reports have shown that this chemokine moderates remyelination and synaptic plasticity (Merino, Bellver‐Landete, Oset‐Gasque, & Cubelos, ) and, in the present context, its pharmacological inhibition (Azizi, Khannazer, & Mirshafiey, ) alleviates the release of inflammatory mediators in both sciatic nerve injury and bone cancer models (Shen et al, ) as well as NMDA receptor‐mediated neurotoxicity (Sanchez et al, ).…”

A pivotal role for Interferon-α receptor-1 in neuronal injury induced by HIV-1

“…Our previous studies have shown that neurons display the highest baseline levels of phosphorylated p38 MAPK in the mixed neuro-glial cell populations [17,34]. In an in vitro approach using cerebrocortical cell cultures, we found that inhibition of ERK1/2 activation with increasing concentrations of the ERK kinase (MEK) inhibitor PD98059 caused neurotoxicity to a similar extent as HIVgp120 (Fig.…”

“…The results of the RT 2 Profiler arrays were further interrogated using Ingenuity Pathway Analysis software (IPA; Ingenuity® Systems, www.ingenuity.com; build version: 486617 M; content version: 46901286; release date: 2018- [11][12][13][14][15][16][17][18][19][20][21]. The core analysis function was employed for identification of functional and biological gene networks, upstream regulators as described previously with some modifications [15,16,18].…”

“…These factors induce neuronal injury, including dendritic and synaptic damage, and eventually apoptosis in the frontal cortex, hippocampus, substantia nigra, putamen, basal ganglia, and cerebellum [8,[11][12][13][14]. The key neuropathological features observed in NeuroHIV are astrocytosis, microgliosis, multinucleated giant cells, infiltration of macrophages, decreased synaptic and dendritic density, and frank loss of neuronal cells [8,[11][12][13][14][15][16][17][18].…”

The diversified function and potential therapy of ectopic olfactory receptors in non‐olfactory tissues

“…The phosphorylation of p38 MAPK might be associated with a transient intracellular Ca 2+ increase in tumor cell. Studies also suggest blockade of Ca 2+ channels abrogate an increase of active p38 MAPK in CXCL12‐induced neurotoxicity (Sanchez et al, ). A transient increase of intracellular Ca 2+ may become a new target for tumor diseases.…”