Monosodium Urate Crystal-Induced Pyroptotic Cell Death in Neutrophil and Macrophage Facilitates the Pathological Progress of Gout

Area of Science:

• Immunology
• Cell Biology
• Rheumatology

Background:

• Monosodium urate (MSU) crystal deposition is central to gout pathogenesis.
• Neutrophil and macrophage activation by MSU crystals drives joint inflammation.
• The role of MSU crystal physicochemical properties in inducing cell death remains unclear.

Purpose of the Study:

• To investigate the role of pyroptosis in gout pathogenesis.
• To explore how MSU crystal size influences cell death and inflammatory responses.
• To evaluate dimethyl fumarate (DMF) as a potential therapeutic agent for gout.

Main Methods:

• Synthesis of MSU crystals with varying sizes.
• Assessment of pyroptosis in bone marrow-derived neutrophils (BMNs) and macrophages (BMDMs).
• Analysis of NLRP3 inflammasome, caspase-1 activation, and N-GSDMD formation.
• Evaluation of neutrophil extracellular trap (NET) and aggregated NET (aggNET) formation.
• Inhibition studies using dimethyl fumarate (DMF) in cell cultures and a gout mouse model.

Main Results:

• MSU crystals induce size-dependent pyroptotic cell death in BMNs and BMDMs via NLRP3 inflammasome activation.
• MSU crystal size dictates the formation of NETs and aggNETs, influenced by interleukin-1β (IL-1β).
• Dimethyl fumarate (DMF) effectively inhibits MSU crystal-induced pyroptosis and alleviates acute gout inflammation in mice.

Conclusions:

• MSU crystal-induced pyroptosis in neutrophils and macrophages is a critical driver of gout pathology.
• Targeting pyroptosis, specifically N-GSDMD oligomerization with DMF, offers a promising therapeutic strategy for gout.