| First Author | Xing B | Year | 2011 |
| Journal | Mol Neurodegener | Volume | 6 |
| Pages | 84 | PubMed ID | 22185458 |
| Mgi Jnum | J:318770 | Mgi Id | MGI:6858166 |
| Doi | 10.1186/1750-1326-6-84 | Citation | Xing B, et al. (2011) Microglial p38alpha MAPK is critical for LPS-induced neuron degeneration, through a mechanism involving TNFalpha. Mol Neurodegener 6:84 |
| abstractText | BACKGROUND: The p38alpha 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 p38alpha MAPK isoform in microglia-dependent neuron damage, we used primary microglia from wild-type (WT) or p38alpha 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 p38alpha-deficient microglia were protected against LPS-induced synaptic loss, neurite degeneration, and neuronal death. The involvement of the proinflammatory cytokine TNFalpha was demonstrated by the findings that p38alpha KO microglia produced much less TNFalpha in response to LPS compared to WT microglia, that adding back TNFalpha to KO microglia/neuron co-cultures increased the LPS-induced neuron damage, and that neutralization of TNFalpha in WT microglia/neuron co-cultures prevented the neuron damage. These results using cell-selective, isoform-specific KO mice demonstrate that the p38alpha 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 p38alpha MAPK signaling leads to neuron damage is through up-regulation of the proinflammatory cytokine TNFalpha. CONCLUSIONS: The data suggest that selective targeting of p38alpha MAPK signaling should be explored as a potential therapeutic strategy for CNS disorders where overproduction of proinflammatory cytokines is implicated in disease progression. |
