Abstract
Japanese encephalitis virus (JEV) targets central nervous system, resulting in neuroinflammation with typical features of neuronal death along with hyper activation of glial cells. Exploring the mechanisms responsible for the JEV-caused inflammatory response remains a pivotal area of research. In the present study, we have explored the function of p21-activated kinase 4 (PAK4) in JEV-mediated inflammatory response in human astrocytes. The results showed that JEV infection enhances the phosphorylation of PAK4 in U251 cells and mouse brain. Knockdown of PAK4 resulted in decreased expression of inflammatory cytokines that include tumor necrosis factor alpha, interleukin-6, interleukin-1β, and chemokine (C-C motif) ligand 5 and interferon β upon JEV infection, suggesting that PAK4 signaling promotes JEV-mediated inflammation. In addition, we found that knockdown of PAK4 led to the inhibition of MAPK signaling including ERK, p38 MAPK and JNK, and also resulted in the reduced nuclear translocation of NF-κB and phosphorylation of AP-1. These results demonstrate that PAK4 signaling actively promotes JEV-mediated inflammation in human astrocytes via MAPK-NF-κB/AP-1 pathway, which will provide a new insight into the molecular mechanism of the JEV-induced inflammatory response.
Highlights
Japanese encephalitis virus (JEV) is a mosquito-borne virus belonging to the Flaviviridae family of the viruses
These results suggest that JEV-infection can induce the activation of p21-activated kinase 4 (PAK4) in astrocytes
We found that JEV infection significantly induced the expression of inflammatory cytokines and IFNβ, whereas knockdown of PAK4 remarkably reduced the levels of these cytokines elicited by JEV (Figure 2B), suggesting that PAK4 positively regulated the inflammatory response induced by JEV in astrocytes
Summary
Japanese encephalitis virus (JEV) is a mosquito-borne virus belonging to the Flaviviridae family of the viruses. Role of PAK4 in JEV-Mediated Neuroinflammation of inflammatory cells, rampant production of proinflammatory cytokines, and neuropathy are the idiosyncratic features of JE (German et al, 2006; Ghoshal et al, 2007). It has been shown that JEV can infect astrocytes and microglia, and these glial cells may serve as long-standing reservoir for JEV (Chen et al, 2000, 2004; Thongtan et al, 2010). The production of various proinflammatory mediators has been implicated in the process of activation of microglia and astrocytes following JEV infection (Chen et al, 2000; Bhowmick et al, 2007; Ghoshal et al, 2007). The molecular mechanisms underlying the JEV-caused inflammatory response in astrocytes are largely unclear
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