Chronic unpredictable stress abrogates the endotoxin tolerance induced by repeated peripheral LPS challenge via the TLR4 signaling pathway

Abstract

Endotoxin tolerance is induced by exposure to a repeated LPS challenge. Stress can exacerbate LPS-induced inflammation in the mouse hippocampus. However, the effects of stress on endotoxin tolerance have not been elucidated. The present experiments were designed to assess whether tolerance could be induced in the hippocampus by intraperitoneal injection of LPS at a dose of 250μg/kg for 7days, to investigate the effects of chronic unpredictable stress (CUS) on LPS-induced tolerance, and to assess underlying mechanisms in male Kunming mice. The levels of IL-1β in the hippocampus increased to a plateau after 4days of LPS injection. When the CUS protocol was performed with concurrent LPS injections for 7days, body weight decreased, and IL-1β expression in the hippocampus increased simultaneously. The expression of TLR4-MyD88-NF-κB signaling molecules and their negative regulators (PI3K, Akt) were also analyzed on day 7 after the last injection. The mRNA expression of TLR4 and MyD88 and the protein levels of TLR4 and NF-κBp65 were significantly increased, but the protein levels of PI3K and p-Akt were significantly decreased in the hippocampus of the mice. In conclusion, our findings show that endotoxin tolerance in the hippocampus was induced after four days of peripheral LPS challenge at a dose of 250μg/kg per day, and CUS abrogated this effect. CUS abolished endotoxin tolerance by reducing PI3K-mediated inhibition of TLR4-MyD88-NF-κB signaling pathways.