NLRP3 inflammasome-mediated neutrophil recruitment and hypernociception depend on leukotriene B4 in a murine model of gout

Objective Deposition of monosodium urate monohydrate (MSU) crystals in the joints promotes an intense inflammatory response and joint dysfunction. This study evaluated the role of the NLRP3 inflammasome and 5‐lipoxygenase (5‐LOX)–derived leukotriene B4 (LTB4) in driving tissue inflammation and hyper...

Full description

Saved in:
Bibliographic Details
Published in:Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2012-02, Vol.64 (2), p.474-484
Main Authors: Amaral, Flávio A., Costa, Vivian V., Tavares, Livia D., Sachs, Daniela, Coelho, Fernanda M., Fagundes, Caio T., Soriani, Frederico M., Silveira, Tatiana N., Cunha, Larissa D., Zamboni, Dario S., Quesniaux, Valerie, Peres, Raphael S., Cunha, Thiago M., Cunha, Fernando Q., Ryffel, Bernhard, Souza, Daniele G., Teixeira, Mauro M.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Cell adhesion & migration
Crystals
Diseases of the osteoarticular system
Inflammatory joint diseases
Medical research
Medical sciences
Metabolic diseases
Miscellaneous. Osteoarticular involvement in other diseases
Other metabolic disorders
Purines and pyrimidines (gout, hyperuricemia...)
Rodents
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Objective Deposition of monosodium urate monohydrate (MSU) crystals in the joints promotes an intense inflammatory response and joint dysfunction. This study evaluated the role of the NLRP3 inflammasome and 5‐lipoxygenase (5‐LOX)–derived leukotriene B4 (LTB4) in driving tissue inflammation and hypernociception in a murine model of gout. Methods Gout was induced by injecting MSU crystals into the joints of mice. Wild‐type mice and mice deficient in NLRP3, ASC, caspase 1, interleukin‐1β (IL‐1β), IL‐1 receptor type I (IL‐1RI), IL‐18R, myeloid differentiation factor 88 (MyD88), or 5‐LOX were used. Evaluations were performed to assess neutrophil influx, LTB4 activity, cytokine (IL‐1β, CXCL1) production (by enzyme‐linked immunosorbent assay), synovial microvasculature cell adhesion (by intravital microscopy), and hypernociception. Cleaved caspase 1 and production of reactive oxygen species (ROS) were analyzed in macrophages by Western blotting and fluorometric assay, respectively. Results Injection of MSU crystals into the knee joints of mice induced neutrophil influx and neutrophil‐dependent hypernociception. MSU crystal–induced neutrophil influx was CXCR2‐dependent and relied on the induction of CXCL1 in an NLRP3/ASC/caspase 1/IL‐1β/MyD88–dependent manner. LTB4 was produced rapidly after injection of MSU crystals, and this was necessary for caspase 1–dependent IL‐1β production and consequent release of CXCR2‐acting chemokines in vivo. In vitro, macrophages produced LTB4 after MSU crystal injection, and LTB4 was relevant in the MSU crystal–induced maturation of IL‐1β. Mechanistically, LTB4 drove MSU crystal–induced production of ROS and ROS‐dependent activation of the NLRP3 inflammasome. Conclusion These results reveal the role of the NLRP3 inflammasome in mediating MSU crystal–induced inflammation and dysfunction of the joints, and highlight a previously unrecognized role of LTB4 in driving NLRP3 inflammasome activation in response to MSU crystals, both in vitro and in vivo.
ISSN:0004-3591
2326-5191
1529-0131
2326-5205
DOI:10.1002/art.33355