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Why does the gout attack stop? A roadmap for the immune pathogenesis of gout.

Schett G, Schauer C, Hoffmann M, Herrmann M - RMD Open (2015)

Bottom Line: This process is associated with the clinical manifestation of an acute gout attack.Neutrophils having ingested MSU crystals undergo a specific form of cell death called NETosis, which is characterised by the formation of neutrophil extracellular traps (NETs).During this process, DNA is extruded, allowing the dense packaging of MSU crystals as well as the degradation of proinflammatory cytokines, thereby allowing the stopping of the inflammatory process.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology , University of Erlangen-Nuremberg , Erlangen , Germany.

ABSTRACT
Gout is one of the most severe and frequent rheumatic diseases. Clinical manifestations of gout arise from uric acid crystal deposition in the musculoskeletal tissue. At high concentrations of uric acid in the body (hyperuricaemia), needle-shaped monosodium urate (MSU) crystals are formed. The structures are ingested by neutrophils and monocytes and thereby trigger robust activation of the inflammasome, an intracellular protein complex mounting an inflammatory response. Inflammasome activation builds interleukin-1, which acts as a proinflammatory mediator and induces vasodilation, recruitment of additional leucocytes and the expression of proinflammatory cytokines and chemokines. This process is associated with the clinical manifestation of an acute gout attack. Such attacks, however, stop rather rapidly and the process of resolution of inflammation in gout is now better defined. Neutrophils having ingested MSU crystals undergo a specific form of cell death called NETosis, which is characterised by the formation of neutrophil extracellular traps (NETs). During this process, DNA is extruded, allowing the dense packaging of MSU crystals as well as the degradation of proinflammatory cytokines, thereby allowing the stopping of the inflammatory process. Reactive oxygen species are essential for forming NETs and for allowing the resolution of inflammation in gout. This process of NETosis is critical for understanding tophaceous gout, since tophi are composed of NETs and densely packed MSU crystals.

No MeSH data available.


Related in: MedlinePlus

Mechanisms of acute gout attack. Needle-shaped MSU crystals (yellow) are ingested by phagocytes such as monocytes. The high sodium content of the crystals increases intracellular sodium concentrations (yellow dots). To maintain iso-osmolarity, water enters the cell through aquaporins and induces the swelling of the cells. Aside from the dilution of sodium in the cell, water also dilutes potassium, which falls below a critical level for the induction of the inflammasome. Activation of the inflammasome produces large amounts of interleukin 1 β (aggNETs, aggregated neutrophil extracellular traps; MSU, monosodium urate; NETosis, aggregated neutrophil extracellular trap formation).
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RMDOPEN2015000046F1: Mechanisms of acute gout attack. Needle-shaped MSU crystals (yellow) are ingested by phagocytes such as monocytes. The high sodium content of the crystals increases intracellular sodium concentrations (yellow dots). To maintain iso-osmolarity, water enters the cell through aquaporins and induces the swelling of the cells. Aside from the dilution of sodium in the cell, water also dilutes potassium, which falls below a critical level for the induction of the inflammasome. Activation of the inflammasome produces large amounts of interleukin 1 β (aggNETs, aggregated neutrophil extracellular traps; MSU, monosodium urate; NETosis, aggregated neutrophil extracellular trap formation).

Mentions: Conditions which increase uric acid levels in the body (hyperuricaemia), such as increased intake or production of purines, as well as impaired excretion of uric acid by the kidneys, bear the risk that uric acid cannot be kept in solution and starts to precipitate into crystals.1 Concentrations of uric acid over 6.4 mg per decilitre, which exceed its solubilisation limit, allow the precipitation of monosodium urate (MSU) crystals in the tissue. Increased dietary purine intake by, for example, excessive meat and beer consumption, or increased endogenous purine production associated with cell and tissue catabolism during forced diet or tumour cell lysis, are well-known conditions which increase the uric acid level in the body and facilitate the precipitation of MSU crystals. In addition, decline in kidney function due to ageing, disease or drugs, such as diuretics and aspirin, impairs the appropriate excretion of uric acid and therefore also increases the risk for crystal deposition. On the other hand, pharmacological interventions2 are able to lower serum uric acid levels in the body, thereby regaining solubility of uric acid and resolving even already existing MSU crystal deposits.3 Such measures include those which (1) effectively lower the production of uric acid such as the xanthine oxidase inhibitors allopurinol and febuxostat, or (2) those which directly cleave uric acid, such as the recombinant enzyme pegloticase, or (3) those fostering the excretion of uric acid through the kidneys, such as benzbromarone or lesinurad (figures 1–3).


Why does the gout attack stop? A roadmap for the immune pathogenesis of gout.

Schett G, Schauer C, Hoffmann M, Herrmann M - RMD Open (2015)

Mechanisms of acute gout attack. Needle-shaped MSU crystals (yellow) are ingested by phagocytes such as monocytes. The high sodium content of the crystals increases intracellular sodium concentrations (yellow dots). To maintain iso-osmolarity, water enters the cell through aquaporins and induces the swelling of the cells. Aside from the dilution of sodium in the cell, water also dilutes potassium, which falls below a critical level for the induction of the inflammasome. Activation of the inflammasome produces large amounts of interleukin 1 β (aggNETs, aggregated neutrophil extracellular traps; MSU, monosodium urate; NETosis, aggregated neutrophil extracellular trap formation).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4632150&req=5

RMDOPEN2015000046F1: Mechanisms of acute gout attack. Needle-shaped MSU crystals (yellow) are ingested by phagocytes such as monocytes. The high sodium content of the crystals increases intracellular sodium concentrations (yellow dots). To maintain iso-osmolarity, water enters the cell through aquaporins and induces the swelling of the cells. Aside from the dilution of sodium in the cell, water also dilutes potassium, which falls below a critical level for the induction of the inflammasome. Activation of the inflammasome produces large amounts of interleukin 1 β (aggNETs, aggregated neutrophil extracellular traps; MSU, monosodium urate; NETosis, aggregated neutrophil extracellular trap formation).
Mentions: Conditions which increase uric acid levels in the body (hyperuricaemia), such as increased intake or production of purines, as well as impaired excretion of uric acid by the kidneys, bear the risk that uric acid cannot be kept in solution and starts to precipitate into crystals.1 Concentrations of uric acid over 6.4 mg per decilitre, which exceed its solubilisation limit, allow the precipitation of monosodium urate (MSU) crystals in the tissue. Increased dietary purine intake by, for example, excessive meat and beer consumption, or increased endogenous purine production associated with cell and tissue catabolism during forced diet or tumour cell lysis, are well-known conditions which increase the uric acid level in the body and facilitate the precipitation of MSU crystals. In addition, decline in kidney function due to ageing, disease or drugs, such as diuretics and aspirin, impairs the appropriate excretion of uric acid and therefore also increases the risk for crystal deposition. On the other hand, pharmacological interventions2 are able to lower serum uric acid levels in the body, thereby regaining solubility of uric acid and resolving even already existing MSU crystal deposits.3 Such measures include those which (1) effectively lower the production of uric acid such as the xanthine oxidase inhibitors allopurinol and febuxostat, or (2) those which directly cleave uric acid, such as the recombinant enzyme pegloticase, or (3) those fostering the excretion of uric acid through the kidneys, such as benzbromarone or lesinurad (figures 1–3).

Bottom Line: This process is associated with the clinical manifestation of an acute gout attack.Neutrophils having ingested MSU crystals undergo a specific form of cell death called NETosis, which is characterised by the formation of neutrophil extracellular traps (NETs).During this process, DNA is extruded, allowing the dense packaging of MSU crystals as well as the degradation of proinflammatory cytokines, thereby allowing the stopping of the inflammatory process.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine 3 and Institute for Clinical Immunology , University of Erlangen-Nuremberg , Erlangen , Germany.

ABSTRACT
Gout is one of the most severe and frequent rheumatic diseases. Clinical manifestations of gout arise from uric acid crystal deposition in the musculoskeletal tissue. At high concentrations of uric acid in the body (hyperuricaemia), needle-shaped monosodium urate (MSU) crystals are formed. The structures are ingested by neutrophils and monocytes and thereby trigger robust activation of the inflammasome, an intracellular protein complex mounting an inflammatory response. Inflammasome activation builds interleukin-1, which acts as a proinflammatory mediator and induces vasodilation, recruitment of additional leucocytes and the expression of proinflammatory cytokines and chemokines. This process is associated with the clinical manifestation of an acute gout attack. Such attacks, however, stop rather rapidly and the process of resolution of inflammation in gout is now better defined. Neutrophils having ingested MSU crystals undergo a specific form of cell death called NETosis, which is characterised by the formation of neutrophil extracellular traps (NETs). During this process, DNA is extruded, allowing the dense packaging of MSU crystals as well as the degradation of proinflammatory cytokines, thereby allowing the stopping of the inflammatory process. Reactive oxygen species are essential for forming NETs and for allowing the resolution of inflammation in gout. This process of NETosis is critical for understanding tophaceous gout, since tophi are composed of NETs and densely packed MSU crystals.

No MeSH data available.


Related in: MedlinePlus