HMG-CoA Reductase Inhibitors Suppress Monosodium Urate-Induced NLRP3 Inflammasome Activation through Peroxisome Proliferator-Activated Receptor-γ Activation in THP-1 Cells

Peroxisome proliferator-activated receptor gamma (PPAR-gamma) is thought to negatively regulate NLRP3 inflammasome activation. The aim of this study was to identify the inhibitory effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on monosodium urate (MSU) crystal-induced NLRP3 inflammasome activation through the regulation of PPAR-gamma in THP-1 cells. The expression of PPAR-gamma, NLRP3, caspase-1, and interleukin-1 beta (IL-1 beta) in human monocytic THP-1 cells transfected with PPAR-gamma siRNA or not and stimulated with MSU crystals was assessed using quantitative a real time-polymerase chain reaction and Western blotting. The expression of those markers in THP-1 cells pretreated with statins (atorvastatin, simvastatin, and mevastatin) was also evaluated. Intracellular reactive oxygen species (ROS) were measured using H2DCF-DA and flow cytometry analyses. THP-1 cells treated with MSU crystals (0.3 mg/mL) inhibited PARR-gamma and increased NLRP3, caspase-1, and IL-1 beta mRNA and protein expression, and all those changes were significantly reversed by treatment with atorvastatin, simvastatin, or mevastatin. PPAR-gamma activity revealed that MSU crystals suppressed PPAR-gamma activity, which was markedly augmented by atorvastatin, simvastatin, and mevastatin. Transfecting cells with PPAR-gamma siRNA attenuated the inhibitory effect of statins on MSU crystal-mediated NLRP3 inflammasome activation. Statins also significantly reduced the intracellular ROS generation caused by stimulation with MSU crystals. The inhibitory effects of atorvastatin and simvastatin on intracellular ROS generation were reduced in THP-1 cells transfected with PPAR-gamma siRNA. This study demonstrates that PPAR-gamma is responsible for suppressing MSU-mediated NLRP3 inflammasome activation. The inhibitory effect of statins on MSU-induced NLRP3 inflammasome activation depends on PPAR-gamma activity and production and the inhibition of ROS generation.

Automated summary

This study aimed to investigate the inhibitory effect of statins on monosodium urate (MSU) crystal-induced NLRP3 inflammasome activation by regulating PPAR-gamma. The expression of PPAR-gamma, NLRP3, caspase-1, and IL-1 beta in THP-1 cells treated with statins and stimulated with MSU crystals was assessed. Treatment with statins reversed the changes in gene and protein expression caused by MSU crystal stimulation. The study demonstrated the involvement of PPAR-gamma in suppressing MSU-mediated NLRP3 inflammasome activation and the inhibitory effect of statins on this activation through the regulation of PPAR-gamma activity and ROS generation.