Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages
Fikri Taufiq, Peili Li, Masanari Kuwabara, Yasutaka Kurata, Toshihiro Hamada, Aiko Takami, Junichiro Miake, Motokazu Tsuneto, Yasuaki Shirayoshi, Kimiyoshi Ichida, Haruaki Ninomiya, Satoshi Miyazaki, Einosuke Mizuta, Akira Ohtahara, Shinobu Sugihara, Kazuhíde Oginö, Masahiko Kato, Kazuhiro Yamamoto, Tetsuya Yamamoto, Ichiro Hisatome
Abstract
Background：When macrophages are primed by lipopolysaccharides, mono sodium urate (MSU) crystals activate NLRP3 inflammasomes and promote IL-1β and IL-18 production after phagocytosis of MSU. It was previously reported that anti-IL-1β antibodies suppress symptoms of gout and the occurrence of cardiovascular disease. Thus, inhibition of NLRP3 inflammasomes, which produce IL-1β and IL-18, may be a novel therapeutic strategy against these diseases. Purpose：To reveal the effects of dotinurad, a selective urate reabsorption inhibitor, and other uric acid lowering agents on MSU crystal-induced activation of NLRP3 inflammasomes in macrophages. Methods：Activity of NLRP3 inflammasomes in J774 mouse macrophages was evaluated by quantifying secreted caspase-1 and IL-1β using a western blot and ELISA in both the absence and presence of dotinurad or other uric acid lowering agents. Results：MSU increased protein levels of caspase-1 and IL-1β. This effect was inhibited by a clinical concentration of dotinurad. Neither febuxostat nor allopurinol influenced the levels of caspase-1 and IL-1β, whereas benzbromarone decreased their levels. The inhibitory effects of dotinurad and other uric acid lowering agents on secretions of IL-1β from the macrophages were confirmed by ELISA. Conclusion：Dotinurad, a selective urate reabsorption inhibitor, suppresses MSU-induced activation of NLRP3 inflammasomes in macrophages.