Abstract
Gout is a self-limiting inflammatory arthritis mediated by the precipitation of monosodium urate (MSU) crystals that further activate the NLRP3 inflammasome and initiate a cascade of inflammatory events. However, the key physicochemical properties of MSU crystals that determine the acute phase of gout have not been fully identified. In this study, a library of engineered MSU crystals with well-controlled size and shape is designed to explore their proinflammatory potentials in mediating the pathological progress of gout. It is demonstrated that medium-sized long aspect ratio MSU crystals induce more prominent IL-1β production in vitro due to enhanced cellular uptake and the production of mitochondrial reactive oxygen species (mtROS). The characteristics of MSU crystals are also correlated with their inflammatory potentials in both acute peritonitis and arthritis models. Furthermore, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) is demonstrated to inhibit MSU-induced oxidative burst by removing plasma membrane cholesterol. As a result, it attenuates the inflammatory responses both in vitro and in vivo. Additionally, antioxidant N-acetylcysteine (NAC) is shown to alleviate acute gouty symptom by suppressing oxidative stress. This study identifies the key physicochemical properties of MSU crystals that mediate the pathogenesis of gout, which sheds light on novel design strategies for the intervention of gout.