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Updated: May 26, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglial p38α MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFα
Bin Xing1, Adam D Bachstetter, Linda J Van Eldik
1Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA.
Background:
The p38α MAPK isoform is a well-established therapeutic target in peripheral inflammatory diseases, but the importance of this kinase in pathological microglial activation and detrimental inflammation in CNS disorders is less well understood. To test the role of the p38α MAPK isoform in microglia-dependent neuron damage, we used primary microglia from wild-type (WT) or p38α MAPK conditional knockout (KO) mice in co-culture with WT cortical neurons, and measured neuron damage after LPS insult.
Results:
We found that neurons in co-culture with p38α-deficient microglia were protected against LPS-induced synaptic loss, neurite degeneration, and neuronal death. The involvement of the proinflammatory cytokine TNFα was demonstrated by the findings that p38α KO microglia produced much less TNFα in response to LPS compared to WT microglia, that adding back TNFα to KO microglia/neuron co-cultures increased the LPS-induced neuron damage, and that neutralization of TNFα in WT microglia/neuron co-cultures prevented the neuron damage. These results using cell-selective, isoform-specific KO mice demonstrate that the p38α MAPK isoform in microglia is a key mediator of LPS-induced neuronal and synaptic dysfunction. The findings also provide evidence that a major mechanism by which LPS activation of microglia p38α MAPK signaling leads to neuron damage is through up-regulation of the proinflammatory cytokine TNFα.
Conclusions:
The data suggest that selective targeting of p38α MAPK signaling should be explored as a potential therapeutic strategy for CNS disorders where overproduction of proinflammatory cytokines is implicated in disease progression.
Insights
Targeting p38α MAPK in microglia protects neurons from inflammatory damage in CNS disorders. This kinase mediates neuron and synaptic dysfunction via TNFα, suggesting a therapeutic strategy for neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- p38α MAPK is a known target for peripheral inflammation.
- Its role in microglial activation and CNS inflammation is less understood.
- Investigating p38α MAPK's role in microglia-driven neurotoxicity.
Purpose of the Study:
- To determine the role of the p38α MAPK isoform in microglia-dependent neuronal damage.
- To elucidate the mechanisms underlying this damage in central nervous system (CNS) disorders.
Main Methods:
- Primary microglia from wild-type (WT) or p38α MAPK conditional knockout (KO) mice were used.
- Co-culture system with WT cortical neurons.
- Lipopolysaccharide (LPS) insult to induce inflammation and neuron damage measurement.
Main Results:
- Neurons co-cultured with p38α-deficient microglia were protected from LPS-induced damage.
- p38α KO microglia produced significantly less TNFα (tumor necrosis factor-alpha) in response to LPS.
- TNFα neutralization protected neurons, while TNFα addition exacerbated damage, confirming its role.
Conclusions:
- Microglial p38α MAPK is a key mediator of LPS-induced neuronal and synaptic dysfunction.
- A major mechanism involves TNFα up-regulation.
- Targeting p38α MAPK signaling is a potential therapeutic strategy for CNS disorders involving cytokine overproduction.
