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Mechanosensitive TRPV4 is required for crystal-induced inflammation
- Source :
- Ann Rheum Dis
- Publication Year :
- 2021
-
Abstract
- 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.
- Subjects :
- Adult
Male
Patch-Clamp Techniques
Crystal Arthropathies
Gout
Inflammasomes
THP-1 Cells
medicine.medical_treatment
Immunology
Interleukin-1beta
Arthritis
TRPV Cation Channels
Inflammation
Peripheral blood mononuclear cell
General Biochemistry, Genetics and Molecular Biology
Article
Mice
Rheumatology
Downregulation and upregulation
NLR Family, Pyrin Domain-Containing 3 Protein
medicine
Immunology and Allergy
Animals
Humans
Innate immune system
business.industry
Arthritis, Gouty
Macrophages
Optical Imaging
Synovial Membrane
Nociceptors
Inflammasome
Middle Aged
medicine.disease
Arthralgia
Uric Acid
Cytokine
Leukocytes, Mononuclear
Mechanosensitive channels
medicine.symptom
business
medicine.drug
Subjects
Details
- ISSN :
- 14682060
- Volume :
- 80
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Annals of the rheumatic diseases
- Accession number :
- edsair.doi.dedup.....f77542fac7a9ceb8f5f1af91b7696b3c