Mechanosensitive TRPV4 is required for crystal-induced inflammation

Area of Science:

• Immunology
• Cell Biology
• Rheumatology

Background:

• Crystals activate innate immune cells, triggering inflammatory responses.
• The role of mechanosensitive channels like TRPV4 in crystal-induced inflammation is not fully understood.

Purpose of the Study:

• To investigate the function of the TRPV4 channel in crystal-induced inflammation, focusing on its role in macrophage activation and NLRP3 inflammasome signaling.
• To explore the therapeutic potential of targeting TRPV4 in crystal-induced arthritic conditions.

Main Methods:

• Utilized real-time RT-PCR, RNAscope in situ hybridization, and Trpv4 knockout mice to assess TRPV4 expression.
• Employed whole-cell patch-clamp recording and live-cell Ca2+ imaging to study TRPV4 function in macrophages and human PBMCs.
• Investigated TRPV4's role in NLRP3 inflammasome activation using genetic deletion and pharmacological inhibition in vitro and in vivo models.

Main Results:

• TRPV4 is functionally expressed in mouse synovial macrophages and human PBMCs, with expression upregulated by monosodium urate (MSU) crystals.
• Genetic ablation or pharmacological inhibition of TRPV4 significantly reduced MSU crystal-induced gouty arthritis in mouse models.
• TRPV4 mediates NLRP3 inflammasome activation by crystalline materials, leading to interleukin-1β production and subsequent inflammation.
• TRPV1-expressing nociceptor ablation also attenuated MSU crystal-induced gouty arthritis, suggesting a neuroimmune interaction.

Conclusions:

• TRPV4 is a critical mediator of diverse crystal-induced inflammatory responses via NLRP3 inflammasome activation in macrophages.
• TRPV4-expressing macrophages are central to MSU crystal-induced gouty arthritis pathogenesis.
• A neuroimmune crosstalk between TRPV1 nociceptors and TRPV4 macrophages contributes to acute gout flares.