TSG-6 exacerbates myocardial ischemia-reperfusion injury by activating NLRP3 inflammasome and regulating macrophage polarization.

BACKGROUND

Myocardial ischemia-reperfusion injury (MI/RI) is a key cause of cardiac dysfunction in patients with acute myocardial infarction after revascularization, with inflammatory imbalance as the core mediating mechanism. Tumor necrosis factor-α-stimulated gene 6 (TSG-6) exerts both anti-inflammatory and pro-inflammatory effects, yet its specific function and molecular mechanism in MI/RI remain unclear.

METHODS

Mouse models with TSG-6-/-and AAV9-mediated overexpression were constructed, and MI/RI and permanent coronary artery ligation models were established in combination with an in vitro macrophage model. Multiple techniques were used to detect myocardial infarct size, cardiac function, molecular expression and cellular function. With the help of NF-κB inhibitors, reactive oxygen species scavengers and Nlrp3 knockout models, the molecular pathway by which TSG-6 regulates MI/RI was explored.

RESULTS

Myocardial TSG-6 in mice was upregulated in a time-dependent manner after MI/RI. Knockout TSG-6 alleviated myocardial injury, improved cardiac function and survival rate in mice, whereas overexpression aggravated myocardial infarction and heart failure. In vitro experiments, TSG-6 activated the macrophage NLRP3 inflammasome in a time- and concentration-dependent manner: it activated the priming signal through the NF-κB/P65 pathway and induced mitochondrial oxidative stress damage to promote its activation. Meanwhile, TSG-6 promoted macrophage polarization toward the M1 phenotype via a NLRP3-dependent mechanism, and NLRP3 knockout reversed this effect.

CONCLUSIONS

TSG-6 exerts pro-inflammatory and pro-injurious effects in MI/RI. Through the dual signals of activating the NF-κB pathway and inducing mitochondrial damage, it promotes the activation of the NLRP3 inflammasome and M1 polarization of macrophages, thereby exacerbating MI/RI. This study clarified the function and mechanism of TSG-6 in regulating MI/RI, laying a theoretical foundation for targeted therapy of myocardial protection.