Sagar Gaikwad, Divyesh Patel, Naveen C. R. and Reena Agrawal-Rajput
Identifying signal transduction pathways and understanding their role in microglia-mediated neuroinflammation and neurotoxicity may provide clinical benefits in neurodegenerative diseases. Microglia activation and inflammation is the first line of defense mechanism by the host to remove pathogen/injurious stimuli and initiate the tissue healing process. Inflammation should be tightly regulated. However, dysregulation leads to ‘bystander’ tissue damage in most neurodegenerative diseases. Evidence suggests that activated microglia excessively secretes chronic neurotoxic factors, including TNF-α, IL1-β, NO and reactive oxygen species (ROS), driving progressive neurotoxicity. The present study provides the molecular mechanisms involved in TLR4 mediated excessive inflammatory responses by microglia. We used LPS stimulated BV2 murine microglia cells, as an in vitro model system to examine TLR4 induced microglia-mediated chronic neuroinflammation. Here we demonstrate that β-amyloid and LPS enhanced TLR4 expression on microglia. LPS stimulation significantly enhanced inflammatory cytokines by microglia in time and dose dependent manner at mRNA and protein levels. Subsequently, phosphorylation of PI3 kinase was observed but it is partially involved in inflammation regulation. In addition, TLR4 activation markedly induces phosphorylation of JNK 1/2, p38 and ERK1/2 MAPKs. Our study revealed that JNK 1/2 and p38 MAPK are crucial players during TLR4 mediated inflammation and neurotoxicity. In addition, combined inhibition of p38 and JNK synergistically increases neuroprotection against Aβ induced neurotoxicity. In conclusion, our findings suggest that TLR4 activation by LPS and β-amyloid significantly increases inflammation while p38 MAPK and JNK 1/2 inhibition provides neuroprotection through negative regulation of NF-κB. Thus p38 MAPK and JNK 1/2 are good therapeutic targets in inflammatory neurodegenerative diseases like Alzheimer’s disease.
