GTS-21 ameliorates polymicrobial sepsis-induced hepatic injury by modulating autophagy through α7nAchRs in mice

Abstract

Background: Previous studies showed that GTS-21, a selective alpha 7 nAchR agonist, can trigger anti-inflammatory effects and improve the survival of septic animals. However, whether GTS-21 affects autophagy responses remains unclear. Here, we tested the hypothesis that GTS-21 ameliorates sepsis-induced hepatic injury by modulating autophagy in mice.

Method: C57BL/6 male mice were randomly separated and categorized into four groups: the sham group, and CLP group subjected to caecal ligation and puncture (CLP, a model of polymicrobial sepsis). The CLP + GTS-21 group was administered GTS-21 immediately after CLP challenge. α-Bungarotoxin (an alpha 7 nAchR antagonist) was injected before CLP was performed, and then, after CLP challenge, GTS-21 was administered to α-BGT + CLP + GTS-21 group. The hepatic tissue and blood samples were harvested 6 h after the operation.

Results: CLP challenge increased TNF-α and IL-6 production, and hepatic enzyme alanine aminotransferase and aspartate transaminase levels. CLP also elevated the expression of hepatic LC3-II, sequestosome-1/p62, Atg7 and Atg5. The administration of GTS-21 inhibited pro-inflammatory cytokine production and hepatic enzymatic marker expression, promoted the expression of LC3-II, Atg7, Atg5, and decreased the expression of p62, which could be reversed by α-BGT treatment.

Conclusion: Our findings suggested that α7nAchR is involved in diminishing hepatic damage by inhibiting inflammatory responses and improving autophagy in mice with polymicrobial sepsis.

Keywords: Alpha 7 nicotinic acetylcholine receptor; Autophagy; Caecal ligation and puncture; Cholinergic anti-inflammatory pathway.