CD137 signaling aggravates myocardial ischemia-reperfusion injury by inhibiting mitophagy mediated NLRP3 inflammasome activation.

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.

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.