Intracardiac administration of neutrophil protease cathepsin G activates noncanonical inflammasome pathway and promotes inflammation and pathological remodeling in non-injured heart

Background: Inflammatory serine proteases (ISPs) play an important role in cardiac repair after injury through hydrolysis of dead cells and extracellular matrix (ECM) debris. Evidence also suggests an important role of ISPs in the coordination of the inflammatory response. However, the effect of ISPs on inflammation is obfuscated by the confounding factors associated with cell death and inflammatory cell infiltration induced after cardiac injury. This study investigated whether neutrophil-derived cathepsin G (Cat.G) influences inflammation and remodeling in the absence of prior cardiac injury and cell death. Methods and results: Intracardiac catheter delivery of Cat.G (1 mg/kg) in rats induced significant left ventricular (LV) dilatation and cardiac contractile dysfunction at day 5, but not at day 2, post-delivery compared to vehicle-treated animals. Cat.G delivery also significantly increased matrix metalloprotease activity and collagen and fibronectin degradation at day 5 compared to vehicle-treated rats and these changes were associated with increased death signaling pathways and myocyte apoptosis. Mechanistic analysis shows that Cat.G-treatment induced potent chemotactic activity in hearts at day 2 and 5 post-delivery, characterized by processing and activation of interleukin (IL)-1 beta and IL-18, stimulation of inflammatory signaling pathways and accumulation of myeloid cells when compared to vehicle-treated rats. Cat.G-induced processing of IL-1 beta and IL-18 was independent of the canonical NLRP-3 inflammasome pathway and treatment of isolated cardiomyocytes with inhibitors of NLRP-3 or caspase-1 failed to reduce Cat.G-induced cardiomyocyte death. Notably, rats treated with IL-1 receptor antagonist (IL-1Ra) show reduced inflammation and improved cardiac remodeling and function following Cat.G delivery. Conclusions: Cat.G exerts potent chemoattractant and pro-inflammatory effects in non-stressed or injured heart in part through processing and activation of IL-1 family cytokines, subsequently leading to adverse cardiac remodeling and function. Thus, targeting ISPs could be a novel therapeutic strategy to reduce cardiac inflammation and improve cardiac remodeling and function after injury or stress.