Wednesday, 03 March 2021 12:35

Decoy Receptor 3 Inhibits Monosodium Urate-Induced NLRP3 Inflammasome Activation via Reduction of Reactive Oxygen Species Production and Lysosomal Rupture

Shie-Liang Hsieh
Frontiers in immunology
March 03, 2021

SU crystal-induced NLRP3 inflammasome activation in the macrophages and in mice. In bone marrow-derived macrophages, THP-1 and U937 cells,we found that theMSU crystal-induced secretion of IL-1b and activation of NLRP3 were suppressed by both DcR3.Fc and HBD.Fc. The suppression of the MSUinduced NLRP3 inflammasome activation is accompanied by the inhibition of lysosomal rupture, mitochondrial production of the reactive oxygen species (ROS), expression of cathepsins, and activity of cathepsin B, without affecting the crystal uptake and the expression of NLRP3 or pro-IL-1b. In the air pouchmicemodel of gout,MSU induced less amounts of IL-1b and chemokines secretion, an increasedM2/M1macrophage ratio, and a reduction of neutrophil recruitment in DcR3-transgenic mice, which expresses DcR3 in myeloid cells. Similarly, the mice intravenously treated with DcR3.Fc or HBD.Fc displayed less inflammation response. These findings indicate that HBD of DcR3 can reduce MSU crystal-induced NLRP3 inflammasome activation via modulation of mitochondrial and lysosomal functions. Therefore, we, for the first time, demonstrate a new therapeutic potential of DcR3 for the treatment of gout.

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