Verteporfin attenuates NLRP3 inflammasome activation to alleviate gout arthritis flares.

BACKGROUND: Gout arthritis (GA) is an inflammatory disorder characterized by the deposition of monosodium urate (MSU) crystals within synovial joints due to increased urate concentrations in the body. The NLRP3 inflammasome drives a majority of the inflammatory response to MSU crystals; therefore, we hypothesize pharmaceutical agents that attenuate NLRP3 inflammasome activation could be used to treat GA flares. RESULTS: We screened a drug library containing 875 FDA-approved drugs and identified five drugs that reduced NLRP3 inflammasome activation without causing cytotoxic effects in bone marrow-derived macrophages (BMDM). The best performing and therefore leading candidate, verteporfin, used to treat macular degeneration and other eye disorders, reduced Nlrp3- and Caspase-1-dependent IL-1β and IL-18 secretion by BMDM. Additionally, verteporfin-treated mice showed a marked reduction in paw swelling and pro-inflammatory cytokine/chemokine induction, including inflammasome markers (IL-1β and IL-18), in a MSU-induced mouse model of GA flares. CONCLUSION: Collectively, these data suggest verteporfin is a NLRP3 inflammasome inhibitor that could be repurposed as a treatment for GA.