Abstract
Abstract In gout patients, MSU crystals formed in the joints cause inflammation, and the activation of the NLRP3 inflammasome is believed to mediate these responses. Cathepsins play an important role in crystal-induced NLRP3 activation that results in subsequent speck formation, caspase-1 activation, IL-1β secretion, and pyroptosis. In this study, we investigated if cathepsins can also influence MSU-induced NLRP3 activation in a gout mouse model. VBY-825 is a reversible pan-cathepsin inhibitor, and we found that VBY-825 significantly suppressed IL-1β secretion and LDH levels from peritoneal naïve macrophages upon MSU stimulation in vito. In a mouse peritonitis model, we found that VBY-825 suppressed MSU-induced inflammation when compared to the control treatment. Interestingly, the inflammation demonstrated by histology and MPO activity in the joints was also reduced by VBY-825 treatment in MSU-induced arthritis. These findings suggest that cathepsins play a critical role in MSU-induced inflammation and could potentially be a target for gout treatment.
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