ATP-Activated P2X7R Promote the Attack of Acute Gouty Arthritis in Rats Through Activating NLRP3 Inflammasome and Inflammatory Cytokine Production

OBJECTIVE: To investigate the effect of P2X7R on MSU crystal-induced acute gouty arthritis in rats and its mechanism on inflammatory responses. METHODS: In vivo activation or inhibition of P2X7R was examined in the ATP group or the BBG group of rats, and the control group were injected with PBS. All three groups of rats were injected with MSU in the right joint cavity. The development of acute gouty arthritis was observed and evaluated at 6h, 12h, 24h, 48h and 72h. The clinical manifestations of acute arthritis, the expression level of P2X7R in spleen macrophages, the ability of macrophages to take up YO-PRO-1, and the level of Tregs, Th17 cells and inflammatory cytokines were assessed. Besides, mRNA expression levels of P2X7R, NLRP3 and IL-1β were also detected. RESULTS: After 12h and 24h administration, P2X7R agonist ATP significantly accelerated the development of acute gouty arthritis, while the P2X7R inhibitor BBG had the opposite effect on this process. Activation of P2X7R significantly aggravated the ankle joint arthritis of the rat and promoted the infiltration of neutrophils and macrophages in the synovial tissue. In addition, the expression of P2X7R in macrophages of ATP group, the uptake of YO-PRO-1 and the expression of NLRP3 mRNA were significantly higher than that in other two groups. At 12h or 24h, activation or inhibition P2X7R had a significant effect on the IL-1β, IL-6, IL-17, IL-10 and TGF-β1. The ratios of Treg/Th17 gradually decreased in the First three time points, it was the lowest at 24h. CONCLUSION: Activation of P2X7R by ATP aggravated the development of acute gouty arthritis through P2X7R/NLRP3 pathway, promoted the secretion of related inflammatory cytokines, which affected radio of Tregs/Th17 cells. The whole pathogenesis process appeared a pattern from acute attack to remission in time-dependent trend.