Nimbolide targets RNF114 in treatment of mouse model of acute pneumonia caused by Staphylococcus aureus

Abstract

Objective To explore the mechanism which drives nimbolide (NIM) in treating acute pneumonia caused by Staphylococcus aureus (S. auteus). Methods A mouse model of acute pneumonia caused by S. auteus was constructed through endotracheal intubation. After NIM treatment, the survival rate was observed, the amount of bacteria in the lung was tested by plate culture, and the expression of inflammatory cytokines in the lung tissues was detected with ELISA. After primary cultured peritoneal macrophages (PM) were infected with S. auteus, the effect of NIM on the expression of inflammatory cytokines and activation of inflammatory pathway were studied with ELISA and Western blotting, respectively. The effect of RNF114 knockdown by lentiviral shRNA infection on inflammation responses in PM was explored with ELISA and Western blotting. Results Acute infection of S. auteus in the lung could cause acute death in the mice, while NIM treatment significantly improved the survival rate and down-regulated the levels of inflammatory cytokines in the lung. However, it had no effect on the lung colonization of S. auteus in the short term. The results of in vitro experiments indicated that NIM may regulate RNF114 function to down-regulate the phosphorylation level of ERK, inhibit the activation of MAPK pathway, and thus suppress the expression of inflammatory cytokines. Conclusion NIM may inhibit the activation of MAPK pathway by regulating the function of RNF114, and thus suppress the expression of inflammatory cytokines in the lung, and finally inhibit the death of mice with acute pulmonary hyperinflammation caused by S. auteus.

Keywords

• staphylococcus aureus
• nimbolide
• macrophage
• rnf114