Activation of multiple Toll-like receptors serves different roles in sepsis-induced acute lung injury.

Abstract

The activation of Toll-like receptors (TLRs) is involved in the innate immune response and the acute inflammatory response following sepsis-induced acute lung injury (ALI). Increasing evidence has demonstrated that sepsis-induced ALI may be closely associated with several abnormal TLRs, activated by components of microorganisms. However, the number of TLRs involved in this process and the extent of their involvement has not been fully elucidated. The current study examined the simultaneous activation of four TLRs closely associated with sepsis-induced ALI. The results demonstrated that in contrast to the sham-operated group, the mRNA and protein expression levels of TLR2/4/9 were significantly increased in the cecal ligation and puncture (CLP)-operated group. In addition, TLR2−/−, TLR3−/−, TLR4−/− and TLR9−/− C57BL/6 mice were used to establish a CLP-induced ALI animal model and measure the expression levels of TNF-α and IL-6 in plasma and lung tissue samples. The expression of both TNF-α and IL-6 were significantly decreased in TLR2−/−, TLR4−/− and TLR9−/− mice compared with WT mice. In addition, the results revealed that knockdown of TLR2, 4 or 9 decreased immune cell infiltration and therefore may attenuate lung injury. Furthermore, the overall survival was significantly increased in TLR2−/−, 4−/− and 9−/− CLP-induced ALI mice compared with the WT CLP-induced ALI mice. However, there was no statistical significance between TLR3−/− CLP-induced ALI and WT CLP-induced ALI in the current study. Taken together, these results suggest that in the sepsis-induced ALI model, several TLRs are upregulated and participate in the inflammatory response. Therefore, inhibition of multiple TLRs including TLR2, 9, and especially TLR4 simultaneously, but not TLR3, may be a potential therapeutic target for the treatment of sepsis-induced ALI.