GPR30 negatively regulates inflammation in gout by inhibiting IL-1β production

Background: Gout is the most common inflammatory arthritis induced by monosodium urate crystal (MSU) precipitation.The incidence of gout attack was significantly higher in men than women, indicating the important role of oestrogen system in pathogenesis of gout, but the specific mechanisms underlying remained to be explored. GPR30, the newly defined estrogen receptor, had been proved participated in regulating inflammation in some diseases. As different estrogen receptors paly different role in inflammation regulation, how GPR30 was involved in the inflammation induced by MSU in gout was still unknown. Methods: In this work, we investigated the function of GPR30 in inflammation induced by MSU in cultured macrophages and in mouse model by using G-1(the agonist of GPR30). We further tested the expression of the TLR and NOD like receptor protein3 (NLRP3), which are the key receptor involved in pathogenesis of gout. ROS and cleaved-caspase-1 expression were also detected to confirm the regulation role in NLRP3 pathway. Seahorse analysis was used to detect the metabolism profile in macrophages by G-1 to investigate the mechanism of GPR30 in inflammation. The relative expression of GPR30 were detected according to the inflammation state to confirm the role of GPR30 in gout. Results: Negative regulation role of G-1 in IL-1β expression and NLRP3 expression were found both in vitro and in vivo. Moreover, the negative regulation of ROS production and NLRP3 as well as cleaved-caspase-1 expression were also found in G-1 stimulated macrophages. Our data also showed that G-1 inhibited aerobic glycolysis in LPS activated macrophages, which might be responsible for IL-1β and NLRP3 expression. Higher expression levels of GPR30 were found in patients with remitted gout inflammation. Conclusion: Together, our data suggested that GPR30 was involved in the negative inflammation regulation induced by MSU and high expression of GPR30 might contribute to part of the mechanism of inflammation remission of gout.