The ROS/GRK2/HIF-1α/NLRP3 Pathway Mediates Pyroptosis of Fibroblast-Like Synoviocytes and the Regulation of Monomer Derivatives of Paeoniflorin

Figure 8

Reactive oxygen species/G protein-coupled receptor kinase 2/hypoxia-inducible factor-1α/nucleotide-binding oligomerization segment-like receptor family 3- (ROS/GRK2/HIF-1α/NLRP3-) mediated pyroptosis in fibroblast-like synoviocytes (FLS) promotes synovitis under hypoxia and the regulation by monomeric derivatives of paeoniflorin (MDP). The level of ROS in FLS rises sharply under hypoxia. Then, excessive ROS promotes GRK2 expression and increases the levels of phosphorylated GRK2 S670, which then increases HIF-1α synthesis. This elevated HIF-1α is transferred to the nucleus to initiate the transcription of the NLRP3 inflammasome. The abnormally high level of NLRP3 inflammasome is activated under hypoxia to form activated cleaved-caspase-1, which, in turn, shears gasdermin D (GSDMD), interleukin- (IL-) 1β, and IL-18 to induce FLS pyroptosis. Monomeric derivative of paeoniflorin (MDP) inhibits the phosphorylation of GRK2 S670 to reduce FLS pyroptosis and relieve synovitis.