Glyburide inhibits the Cryopyrin/Nalp3 inflammasome.
Inflammasomes activate caspase-1 for processing and secretion of the cytokines interleukin-1beta (IL-1beta) and IL-18. Cryopyrin/NALP3/NLRP3 is an essential component of inflammasomes triggered by microbial ligands, danger-associated molecular patterns (DAMPs), and crystals. Inappropriate Cryopyrin activity has been incriminated in the pathogenesis of gouty arthritis, Alzheimer's, and silicosis. Therefore, inhibitors of the Nalp3 inflammasome offer considerable therapeutic promise. In this study, we show that the type 2 diabetes drug glyburide prevented activation of the Cryopyrin inflammasome. Glyburide's cyclohexylurea group, which binds to adenosine triphosphatase (ATP)-sensitive K(+) (K(ATP)) channels for insulin secretion, is dispensable for inflammasome inhibition. Macrophages lacking K(ATP) subunits or ATP-binding cassette transporters also activate the Cryopyrin inflammasome normally. Glyburide analogues inhibit ATP- but not hypothermia-induced IL-1beta secretion from human monocytes expressing familial cold-associated autoinflammatory syndrome-associated Cryopyrin mutations, thus suggesting that inhibition occurs upstream of Cryopyrin. Concurrent with the role of Cryopyrin in endotoxemia, glyburide significantly delays lipopolysaccharide-induced lethality in mice. Therefore, glyburide is the first identified compound to prevent Cryopyrin activation and microbial ligand-, DAMP-, and crystal-induced IL-1beta secretion.
Lamkanfi
Mohamed
M
Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA.
Mueller
James L
JL
Vitari
Alberto C
AC
Misaghi
Shahram
S
Fedorova
Anna
A
Deshayes
Kurt
K
Lee
Wyne P
WP
Hoffman
Hal M
HM
Dixit
Vishva M
VM
D000251:Adenosine Triphosphatases / Q000276:immunology / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005905:Glyburide / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011897:Random Allocation; D012486:Salmonella typhimurium / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000502:physiology
D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D000255:Adenosine Triphosphate; D020170:Caspase 1; D000251:Adenosine Triphosphatases; D005905:Glyburide