Montelukast suppresses NLRP3 inflammasome activation as a potential prophylactic agent against gout arthritis flares

BACKGROUND: Gout arthritis (GA) flares are unexpected bouts of heat, swelling, and redness resulting in excruciating pain caused by monosodium urate (MSU) crystal deposition in the synovial joints. GA flare symptoms occur as a by-product of the inflammatory response as immune cells engulf MSU crystals in the joint. The NLRP3 inflammasome is the major source of the inflammatory response to MSU crystals; therefore, we hypothesize that prophylactic administration of agents that target the NLRP3 inflammasome could be used to suppress GA flares. RESULTS: We previously performed a screen of 875 FDA-approved drugs to identify candidates that suppressed NLRP3 inflammasome activation without causing cytotoxicity in bone marrow-derived macrophages (BMDM). In this study, one of the candidates, montelukast, an anti-asthma drug, significantly suppressed Nlrp3- and Caspase-1-dependent IL-1β and IL-18 secretion by BMDM. Furthermore, in an MSU-induced mouse model of GA flares, treatment with montelukast mitigated pro-inflammatory cytokine/chemokine secretion, including inflammasome-dependent cytokines (IL-1β and IL-18), and edema. CONCLUSIONS: Overall, these data suggest montelukast is a robust suppressor of the NLRP3 inflammasome that could be repurposed as a prophylactic agent to mitigate GA flares.