Abstract
BackgroundThe 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.ResultsWe 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.ConclusionsThe 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.
Highlights
The p38a mitogen activated protein kinase (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
Validation of microglia p38a MAPK deletion in conditional KO mice In the CNS, p38a MAPK is not restricted to microglia; to determine the importance of p38a MAPK in microglia, we used primary microglia isolated from p38a conditional KO mice, where p38a is genetically deficient in microglia [25]
The absence of p38a MAPK did not affect the number of microglia that were isolated from the p38a KO mice
Summary
The p38a 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 p38a MAPK isoform in microglia-dependent neuron damage, we used primary microglia from wild-type (WT) or p38a MAPK conditional knockout (KO) mice in coculture with WT cortical neurons, and measured neuron damage after LPS insult. Extensive evidence, both clinical and preclinical, implicates neuroinflammation and overproduction of proinflammatory cytokines as a contributor to pathophysiology of chronic neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease, and multiple sclerosis [for review, see: [1]]. It is of critical importance to elucidate the mechanisms that are involved in the dysregulated response of microglia which contribute to neuronal damage
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