Sodium overload and water influx activate the NALP3 inflammasome.
The NALP3 inflammasome is activated by low intracellular potassium concentrations [K(+)](i), leading to the secretion of the proinflammatory cytokine IL-1β. However, the mechanism of [K(+)](i) lowering after phagocytosis of monosodium urate crystals is still elusive. Here, we propose that endosomes containing monosodium urate crystals fuse with acidic lysosomes. The low pH in the phagolysosome causes a massive release of sodium and raises the intracellular osmolarity. This process is balanced by passive water influx through aquaporins leading to cell swelling. This process dilutes [K(+)](i) to values below the threshold of 90 mm known to activate NALP3 inflammasomes without net loss of cytoplasmic potassium ions. In vitro, the inhibitors of lysosomal acidification (ammonium chloride, chloroquine) and of aquaporins (mercury chloride, phloretin) all significantly decreased the production of IL-1β. In vivo, only the pharmacological inhibitor of lysosome acidification chloroquine could be used which again significantly reduced the IL-1β production. As a translational aspect one may consider the use of chloroquine for the anti-inflammatory treatment of refractory gout.
Department of Internal Medicine 3, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
Christine
C
Schorn
Benjamin
B
Frey
Kirsten
K
Lauber
Christina
C
Janko
Moritz
M
Strysio
Hildegard
H
Keppeler
Udo S
US
Gaipl
Reinhard E
RE
Voll
Eva
E
Springer
Luis E
LE
Munoz
Georg
G
Schett
Martin
M
Herrmann
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D058847:Inflammasomes / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010586:Phagocytes / Q000166:cytology / Q000187:drug effects; D010587:Phagocytosis / Q000187:drug effects; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D014527:Uric Acid / Q000737:chemistry / Q000378:metabolism; D014867:Water / Q000378:metabolism*
D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D014867:Water; D014527:Uric Acid; D012964:Sodium; D011188:Potassium