leukotriene-b4 and Gout

The leukotrienes (LTs) are a novel group of biologically active mediators derived from arachidonic acid via lipoxygenase enzymes. LTB4 is a potent chemotactic agent for polymorphonuclear leukocytes and in vivo may mediate inflammatory reactions by inducing leukocyte recruitment by mediating indirectly vascular permeability charges and by modulating pain responses. LTC4 and LTD4 collectively account for the biological activity known as slow-reacting substance of anaphylaxis and are potent smooth muscle contracting agents. They may mediate inflammatory reactions by producing changes in blood flow and increases in vascular permeability. Evidence for LT involvement in a number of pathological conditions including diseases such as asthma, psoriasis, ulcerative colitis, and gout is now accumulating.

Topics: Animals; Arthritis, Rheumatoid; Asthma; Colitis, Ulcerative; Gout; Humans; In Vitro Techniques; Inflammation; Leukotriene B4; Neutrophils; Psoriasis; Rabbits; SRS-A

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.. 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.. 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.. 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.

Topics: Animals; Carrier Proteins; Caspase 1; Cytokines; Gout; Hyperalgesia; Inflammasomes; Inflammation; Interleukin-1beta; Leukotriene B4; Macrophages; Male; Mice; Mice, Knockout; Neutrophil Infiltration; Neutrophils; NLR Family, Pyrin Domain-Containing 3 Protein; Reactive Oxygen Species; Synovial Membrane; Uric Acid

Gouty inflammation can be suppressed by an iron chelator. We therefore hypothesized that arthritis associated with sodium urate crystal deposition could follow the incomplete complexation of iron cation with subsequent oxidant generation as the metal cycles through reduced and oxidized states. Urate crystals adsorbed Fe3+ in vitro and crystals collected from a human tophus had significant concentrations of ionizable iron. Urate crystals oxidized deoxyribose to a thiobarbituric acid (TBA)-reactive product, augmented luminol chemiluminescence by neutrophils, released leukotriene B4 from neutrophils, activated complement, and promoted neutrophil chemotaxis. All of these events increased with the concentration of complexed iron and were suppressed by the iron chelator deferoxamine or the .OH scavenger dimethylthiourea. These results suggest that some portion of gouty inflammation after urate crystal deposition could result from the incomplete complexation of iron with subsequent catalytic generation of reactive oxygen species.

Topics: Chemotaxis, Leukocyte; Chlorides; Complement Activation; Crystallization; Deferoxamine; Ferric Compounds; Gout; Humans; In Vitro Techniques; Inflammation; Iron; Kinetics; Leukotriene B4; Neutrophils; Uric Acid

Leukotriene B4 (LTB4), a metabolite of arachidonic acid and a potent cytotaxin, is generated by human peripheral polymorphonuclear leucocytes (PMNs) exposed to monosodium urate crystals (MSU). The leukotriene is present in gouty effusions in concentrations significantly greater than those found in synovial fluid from patients with active rheumatoid arthritis or osteoarthritis. Further metabolism and biological deactivation of LTB4 by PMNs are partly inhibited by MSU. It is concluded that LTB4 is an important chemical mediator in an acute gouty attack.

Topics: Acute Disease; Adult; Aged; Chemotactic Factors; Crystallization; Gout; Humans; Leukotriene B4; Male; Middle Aged; Neutrophils; Synovial Fluid; Uric Acid