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Abstract
Gout is a leading cause of joint inflammation that has been crippling mankind for centuries. Notwithstanding the tremendous progress made in the medical sciences in the recent past, the conventional treatments are suboptimal for gout to this day. So far, we know the inflammation is caused by monosodium urate (MSU) crystals aggravating immune cells, specifically neutrophils and macrophages. It is predominantly neutrophil-driven and neutrophil extracellular traps (NETs) play a major role in regulating inflammation. Our study has led to the novel finding that the P2Y6 receptor antagonist, MRS2578, inhibits MSU crystal-induced NET formation. Other neutrophil functions like superoxide production, calcium mobilization, interleukin-8 (IL-8) release and migration are also retarded. Therefore, understanding the role of P2Y6R may pave the way towards exploring the mechanism involved in regulating the NET-inducing pathway.Additionally, we found that interleukin-1 (IL-1), a prevalent cytokine in gout inflammation, can enhance NET formation (and hence, inflammation) in the presence of MSU crystals. Anti-IL-1 strategies are currently employed to alleviate inflammation in gout patients. Through our efforts we have progressed significantly in the mission to unveil the underlying mechanism involved in MSU crystal-triggered NETs. Our goal is to understand the relevant pathways that will advance our knowledge and will enable the development of effective therapeutic strategies and tools that will be able to prevent gout.