Inflammasome

The inflammasome is a cytosolic protein complex in macrophages and neutrophils, which is stimulated by components of bacteria or by uric acid crystals, Siliciumdioxidkristalle, titanium dioxide crystals or asbestos. This triggers a series of reactions that leads to the activation of caspase -1. Caspase-1 activates pro-inflammatory cytokine interleukin- 1β by cleaving the inactive precursor interleukin- 1β pro. Active interleukin- 1β is secreted by macrophages and triggers the inflammatory response. If the inflammasome activated by bacterial components, the inflammatory response plays an important role in the defense against infection. If, however, the inflammation caused by uric acid crystals, it comes to gout.

The inflammasome is an important component of the innate immune system.

One of the proteins from which the inflammasome is built, is cryopyrin or NALP3. A mutation in the gene CIAS1, which cryopyrin coded leads to a congenital disease that causes fever, rash, joint damage within the first weeks of life to an inflammatory systemic disease primarily of the knee joints, deafness and mental retardation due to chronic meningitis ( meningitis). This syndrome is referred to as " Inflammatory multisystem disease of the newborn " ( Neonatal Onset Multisystem Inflammatory Disease ). The mortality rate is 20%. Treatment with the interleukin -1 receptor antagonist anakinra leads affected to a significant improvement of symptoms and laboratory signs of inflammation.

Other congenital syndromes are caused by mutation of CIAS1 are the familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Both syndromes have a more benign course and are characterized by episodes of rash and systemic signs of inflammation, but there are no changes in the joints, chronic meningitis, and mental retardation.

NALP3 inflammasome activation by sodium urate in patients with gout

Low intracellular potassium concentration [K ] i activates the NALP3Inflammasom, triggering the secretion of proinflammatory cytokine IL- 1β ¬ toric. The mechanism by which sodium urate decrease after phagocytosis [K ] i, has long been unclear. Recently it was reported that endosomes containing sodium urate, fuse with acidic lysosomes. The low pH of the phagolysosomes caused a massive release of sodium and increases the intracellular osmolarity. This is compensated by passive supply of water through aquaporins, which leads to swelling of the cells. Wherein [K ] i is reduced to values ​​below the threshold value of 90mm, wherein the NALP3 inflammasome is activated. In vitro, the inhibitors of lysosomal acidification ( ammonium chloride, chloroquine ) and of aquaporins reduced (mercury chloride, phloretin ) significantly increased the production of IL- 1β. Chloroquine. And in vivo to chloroquine can be used as a pharmacological inhibitor of lysosomal acidification and reduces IL- 1β production significantly. Consequently, it seems sensible to take chloroquine as a potential therapeutic agent of refractory gout in the eye.

Swell

• Immunology
• Protein complex