NLRP3 inflammasome–mediated neutrophil recruitment and hypernociception depend on leukotriene B4in a murine model of gout

Sep 29, 2011Arthritis and rheumatism

Neutrophil buildup and increased pain in gout depend on leukotriene B4 and NLRP3 inflammasome in mice

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Abstract

Injection of monosodium urate crystals into mouse knee joints triggered neutrophil influx and hypernociception.

Neutrophil influx and pain sensitivity following MSU crystal injection were dependent on the CXCR2 receptor and the cytokine CXCL1.
The NLRP3 inflammasome pathway, involving ASC, caspase 1, and IL-1β, was essential for the neutrophil response to MSU crystals.
Leukotriene B(4) production occurred rapidly after MSU crystal injection and was necessary for IL-1β production and chemokine release.
Macrophages generated leukotriene B(4) in response to MSU crystals, which was important for the maturation of IL-1β.
Leukotriene B(4) was associated with reactive oxygen species production and the activation of the NLRP3 inflammasome in response to MSU crystals.

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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 B(4) (LTB(4) ) 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, LTB(4) 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. LTB(4) 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 LTB(4) after MSU crystal injection, and LTB(4) was relevant in the MSU crystal-induced maturation of IL-1β. Mechanistically, LTB(4) 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 LTB(4) in driving NLRP3 inflammasome activation in response to MSU crystals, both in vitro and in vivo.

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NLRP3 inflammasome–mediated neutrophil recruitment and hypernociception depend on leukotriene B4in a murine model of gout

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