Role of toll-like receptor 4 in the regulation of the cell death pathway and neuroinflammation

Abstract

Septic brain injury is a severe disease of the central nervous system and involves alteration of the cell death pathway due to sepsis. Increasing evidence indicates that Toll-like receptor 4 (TLR4) plays a key role in the development of sepsis. Cell death is also thought to contribute to septic brain injury. However, the mechanism that regulates cell death pathways in response to TLR4 in neurons exposed to septic brain injury is unclear. Here, we established a rat model of septic brain injury to evaluate the effect of TLR4 inhibition on cell death pathways. Furthermore, primary neurons with and those without TLR4 inhibition were exposed to lipopolysaccharide (LPS). We found that septic brain injury induction by cecum ligation and puncture evoked autophagy, induced high-mobility group box-1(HMGB1) translocation and increased TLR4 expression. Inhibition of TLR4 also enhanced autophagy and increased nuclear HMGB1 levels in the sepsis-injured rat brain cortex. After LPS treatment in vitro, HMGB1 was released from neurons. This release of HMGB1 could be inhibited using a TLR4 inhibitor. Collectively, these results indicate that modulation of TLR4 may result in the regulation of neuron cell death pathways by regulating autophagy in cortical tissues. Thus, it may represent a potential therapeutic strategy for neuronal protection in septic brain injury.