Crystal structures activate innate immune cells, especially macrophages and initiate inflammatory responses. We aimed to understand the role of the mechanosensitive TRPV4 channel in crystal-induced inflammation. Real-time RT-PCR, RNAscope in situ hybridisation, and Trpv4eGFP mice were used to examine TRPV4 expression and whole-cell patch-clamp recording and live-cell Ca2+ imaging were used to study TRPV4 function in mouse synovial macrophages and human peripheral blood mononuclear cells (PBMCs). Both genetic deletion and pharmacological inhibition approaches were used to investigate the role of TRPV4 in NLRP3 inflammasome activation induced by diverse crystals in vitro and in mouse models of crystal-induced pain and inflammation in vivo. TRPV4 was functionally expressed by synovial macrophages and human PBMCs and TRPV4 expression was upregulated by stimulation with monosodium urate (MSU) crystals and in human PBMCs from patients with acute gout flares. MSU crystal-induced gouty arthritis were significantly reduced by either genetic ablation or pharmacological inhibition of TRPV4 function. Mechanistically, TRPV4 mediated the activation of NLRP3 inflammasome by diverse crystalline materials but not non-crystalline NLRP3 inflammasome activators, driving the production of inflammatory cytokine interleukin-1β which elicited TRPV4-dependent inflammatory responses in vivo. Moreover, chemical ablation of the TRPV1-expressing nociceptors significantly attenuated the MSU crystal-induced gouty arthritis. In conclusion, TRPV4 is a common mediator of inflammatory responses induced by diverse crystals through NLRP3 inflammasome activation in macrophages. TRPV4-expressing resident macrophages are critically involved in MSU crystal-induced gouty arthritis. A neuroimmune interaction between the TRPV1-expressing nociceptors and the TRPV4-expressing synovial macrophages contributes to the generation of acute gout flares.
- immune system diseases
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ZL and LC are joint first authors.
Handling editor Josef S Smolen
ZL and LC contributed equally.
Contributors HH, LC and ZL conceived the experiments. LC and ZL performed the experiments and analyzed the data. JF, ZX, JL and XH. assisted with Ca2+ imaging and whole-cell patch-clamp recording. FW and BK assisted with flow cytometry. JL and PY assisted with RAN scope. YZ, XY, LD, ZZ, LC and PL assisted with behavioural assays. ZL assisted with collection of human blood samples. LD, PL, PY and ZL assisted with Western blot and in situ hybridisation. BK, RS and KL assisted with manuscript preparation. LC, JF and HH supervised the project and wrote the manuscript. All authors discussed the manuscript, commented on the project and contributed to manuscript preparation.
Funding This work was supported by grants from the National Institutes of Health R01DK103901, R01AR077183, and R01AA027065 to HH.
Competing interests BK has served as a consultant for AbbVie, ABRAX Japan, Almirall, Cara Therapeutics, Maruho, Menlo Therapeutics, Pfizer, and Third Rock Ventures. BK is also founder, chief scientific officer, and stockholder of Nuogen Pharma and stockholder of Locus Biosciences.
Provenance and peer review Not commissioned; externally peer reviewed.
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