Liraglutide alleviates sepsis-induced cardiac dysfunction by modulating macrophage polarization via STING/P65 pathway

Sepsis-induced cardiac dysfunction is a severe complication of sepsis, characterized by impaired heart function and high mortality. A key contributor to this pathology is cardiomyocyte pyroptosis, a highly inflammatory form of programmed cell death, alongside dysregulated macrophage polarization. Current therapeutic strategies often fall short in effectively mitigating this cardiac damage. Glucagon-like peptide-1 receptor (GLP-1R) agonists, like Liraglutide, are known for their metabolic benefits and anti-inflammatory properties, making them a promising candidate for exploring novel mechanisms in inflammatory conditions beyond their primary indications.

Researchers applied Liraglutide (Lira, 100ug/kg/12h, 3 days) pretreatment to a lipopolysaccharide (LPS, 10 mg/kg)-induced sepsis mouse model to evaluate its impact on cardiomyocyte pyroptosis and macrophage polarization. They also utilized conditioned medium (CM) from Lira-pretreated peritoneal macrophages (PMs) on H9c2 cardiomyocytes in vitro. Mechanistic studies involved STING knockdown and activation (using DMXAA) in M1 PMs, alongside assessing P65 nuclear translocation to elucidate the underlying signaling pathways.

Activated GLP-1R significantly inhibited cardiomyocyte pyroptosis and suppressed M1 macrophage polarization in the hearts of septic mice. Conditioned medium from Lira-pretreated peritoneal macrophages effectively 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, a STING agonist, could block the inhibitory effect of Lira on M1 macrophages and partially reverse the suppression of H9c2 pyroptosis by CM. Activation of GLP-1R on macrophages suppressed 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.