Novel inhibitory effects of dotinurad, a selective urate reabsorption inhibitor, on urate crystal-induced activation of NLRP3 inflammasomes in macrophages

Abstract

Background: When macrophages are primed by lipopolysaccharides, mono sodium urate (MSU) crystals activate NLRP 3 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 crystalinduced 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.

Review of Urate-Lowering Therapeutics: From the Past to the Future

“…Dotinurad is a SURI (Fuji Yakuhin, Chiba, Japan) that was approved in Japan 2020 ( Taniguchi et al, 2019 ). In vitro studies reported that dotinurad also inhibits the NLRP3 inflammasome ( Taufiq et al, 2020 ). Two phase 2 studies demonstrated dose-dependent urate-lowering effects in subjects taking 0.5–4 mg/d of dotinurad ( Kuriyama, 2020 ).…”

Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA)

“…The precise mechanisms responsible for those findings are still unclear. Taufiq et al showed that dotinurad suppressed monosodium urate-induced activation of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 inflammasomes in mouse macrophages [ 36 ]. A recent experimental study also revealed that dotinurad ameliorated insulin resistance and hepatic steatosis through the suppression of reactive oxygen species (ROS) production and brown adipose tissue whitening in high-fat diet-induced obese mice [ 37 ].…”