NLRP3 inflammasome–mediated neutrophil recruitment and hypernociception depend on leukotriene B4 in a murine model of gout
| Autor: | Mauro M. Teixeira, Fernando Q. Cunha, Daniele G. Souza, Bernhard Ryffel, Thiago M. Cunha, Dario S. Zamboni, Frederico Marianetti Soriani, Valérie F. J. Quesniaux, Lívia D. Tavares, Raphael S. Peres, Flávio A. Amaral, Caio T. Fagundes, Daniela Sachs, Vivian Vasconcelos Costa, Larissa D. Cunha, Tatiana N. Silveira, Fernanda M. Coelho |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Chemokine Gout Inflammasomes Neutrophils Leukotriene B4 medicine.medical_treatment Interleukin-1beta Immunology Caspase 1 Inflammation Mice chemistry.chemical_compound Rheumatology NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Immunology and Allergy Pharmacology (medical) Caspase Mice Knockout biology Macrophages Synovial Membrane Inflammasome ANTIGOTOSOS Molecular biology Uric Acid CXCL1 Cytokine Neutrophil Infiltration chemistry Hyperalgesia biology.protein Cytokines medicine.symptom Carrier Proteins Reactive Oxygen Species medicine.drug |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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