GLP-1R activation alleviated sepsis-induced cardiac dysfunction by modulating macrophage polarization via the STING/ P65 pathway.

Activated glucagon-like peptide-1 receptor (GLP-1R) could alleviate sepsis-induced cardiomyocyte pyroptosis and regulate the polarization of M1 macrophages. However, the direct effect and mechanism of GLP-1R-mediated macrophage polarization on cardiomyocyte pyroptosis remain unclear. In our study, Liraglutide (Lira, 100ug/kg/12 h, 3 days) pretreatment was applied to a lipopolysaccharide (LPS, 10 mg/kg)-induced sepsis mouse model to investigate its efficacy in modulating cardiomyocyte pyroptosis and macrophage polarization. Our results showed that activated GLP-1R could inhibit cardiomyocyte pyroptosis, and suppress macrophage polarization in mice heart. Conditioned medium (CM) from Lira-pretreated peritoneal macrophages (PMs) inhibited the expression of pyroptosis-related proteins in H9c2 cells. Mechanistically, activated GLP-1R downregulated STING expression in M1 PMs. Furthermore, STING knockdown enhanced the inhibitory effect of Lira on M1 macrophages and strengthened the suppression of pyroptosis in H9c2 cells by CM. Conversely, DMXAA (STING agonist) could block the inhibitory effect of Lira on M1 macrophages and partially reverse the suppression of H9c2 pyroptosis by CM. Furthermore, activation of GLP-1R on macrophages could suppress P65 nuclear translocation by modulating STING expression. Subsequent in vivo studies revealed that STING pathway activation markedly attenuated the cardioprotective effects of Lira in a murine sepsis model. These results demonstrated that activation of GLP-1R inhibited M1 macrophage polarization, thereby alleviating cardiomyocyte pyroptosis. Additionally, the regulation of macrophage polarization by GLP-1R is partially mediated through the STING/P65 pathway.