Buformin alleviates sepsis-induced acute lung injury via inhibiting NLRP3-mediated pyroptosis through an AMPK-dependent pathway.

Bohao Liu, Zhong Wang, Ruyuan He, Rui Xiong, Guorui Li, Lin Zhang, Tinglv Fu, Chenyuan Li, Ning Li, Qing Geng

Clinical science (London, England : 1979) 2022 Feb 25

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NOD-like receptor family pyrin domain containing 3 (NLRP3)-mediated macrophage pyroptosis plays an important role in sepsis-induced acute lung injury (ALI). Inhibition of pyroptosis may be a way to alleviate inflammation as well as tissue damage triggered after lipopolysaccharide (LPS) stimulation. The aim of the present study was to explore whether buformin (BF), a hypoglycemic agent, could alleviate sepsis-induced ALI by inhibiting pyroptosis. Wildtype C57BL/6 mice were randomly divided into control group, BF group, LPS group and LPS+BF group. BF group and LPS+BF group were pretreated with BF at a dose of 25 mg/kg, and the changes were observed. In addition, BF was used to interfere with THP-1 cells. The therapeutic effect of BF has been verified by intraperitoneal injection of BF in vivo after LPS stimulation. Inflammation and injury was significantly reduced in BF pretreated mice, and the indexes related to pyroptosis were suppressed. The phosphorylation of AMP-activated protein kinase (AMPK) in lung tissues of mice in the BF and LPS+BF groups was significantly higher. In THP-1 cells, the AMPK inhibitor, Compound C was added to demonstrate that BF worked via AMPK to inhibit NLRP3 inflammasome. It was further demonstrated that BF up-regulated autophagy, which in turn promoted NLRP3 inflammasome degradation. On the other hand, BF decreased NLRP3 mRNA level by increasing nuclear factor-erythroid 2 related factor 2 (Nrf2). And BF showed a therapeutic effect after LPS challenge. Our study confirmed that BF inhibited NLRP3-mediated pyroptosis in sepsis-induced ALI by up-regulating autophagy and Nrf2 protein level through an AMPK-dependent pathway. This provides a new strategy for clinical mitigation of sepsis-induced ALI. © 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Citation

Bohao Liu, Zhong Wang, Ruyuan He, Rui Xiong, Guorui Li, Lin Zhang, Tinglv Fu, Chenyuan Li, Ning Li, Qing Geng. Buformin alleviates sepsis-induced acute lung injury via inhibiting NLRP3-mediated pyroptosis through an AMPK-dependent pathway. Clinical science (London, England : 1979). 2022 Feb 25;136(4):273-289