Background
The inflammatory response caused by the NLRP3 is closely related to the formation of myocardial ischemia-reperfusion injury. Costimulatory receptor CD137 and its ligand play a crucial role in regulating the inflammatory immune response in atherosclerosis, which is the fundamental cause of cardiovascular diseases. However, the roles of CD137 signaling in the process of myocardial ischaemia-reperfusion (IR) injury remain unknown.
Conclusions
Our results reveal that activating CD137 signaling aggravates myocardial IR injury by upregulating NLRP3 inflammasome activation via suppressing mitophagy and promoting mtROS generation.
Methods
Genetic ablation was used to determine the functional significance of CD137 in myocardial IR injury. Expression of CD137 was examined by Western-blot, quantitative real-time polymerase chain reaction, and immunohistochemistry in a murine IR model by coronary artery ligation. Even's blue-TTC staining and echocardiography to evaluate the severity of myocardial IR injury. Furthermore, HL-1 cardiomyocytes treated with agonist-CD137 recombinant protein were used to explore the underlying mechanism in CD137 signaling-induced NLRP3 inflammasome activation in response to hypoxia/reoxygenation or LPS/ATP.
Results
We demonstrated that CD137 knockout significantly improved cardiac function, accompanied by a markedly reduced NLRP3-mediated inflammatory response and IA/AAR which were reversed by mitophagy inhibitor Mdivi-1. Activating CD137 signaling significantly inhibited mitophagy and provoked NLRP3-mediated inflammatory response in H/R-injured or LPS-primed and ATP-stimulated HL-1 cardiomyocytes, the effects of which could be abolished by either anti-CD137 or mitophagy activator FCCP. Besides, mitochondrial ROS was augmented by activating CD137 signaling through the suppression of mitophagy. Conclusions: Our results reveal that activating CD137 signaling aggravates myocardial IR injury by upregulating NLRP3 inflammasome activation via suppressing mitophagy and promoting mtROS generation.