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. 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.