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Glyburide inhibits the Cryopyrin/Nalp3 inflammasome

(2009) JOURNAL OF CELL BIOLOGY. 187(1). p.61-70
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Abstract
Inflammasomes activate caspase-1 for processing and secretion of the cytokines interleukin-1 beta (IL-1 beta) 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-1 beta 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-1 beta secretion.
Keywords
P2X(7) RECEPTOR, BINDING CASSETTE TRANSPORTER, COLD AUTOINFLAMMATORY SYNDROME, NALP3 INFLAMMASOME, ATP BINDING, INSULIN-SECRETION, SULFONYLUREA RECEPTOR, INTERLEUKIN-1-BETA RELEASE, CASPASE-1, MOUSE

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Chicago
Lamkanfi, Mohamed, JL Mueller, AC Vitari, S Misaghi, A Fedorova, K Deshayes, WP Lee, HM Hoffman, and VM Dixit. 2009. “Glyburide Inhibits the Cryopyrin/Nalp3 Inflammasome.” Journal of Cell Biology 187 (1): 61–70.
APA
Lamkanfi, M., Mueller, J., Vitari, A., Misaghi, S., Fedorova, A., Deshayes, K., Lee, W., et al. (2009). Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. JOURNAL OF CELL BIOLOGY, 187(1), 61–70.
Vancouver
1.
Lamkanfi M, Mueller J, Vitari A, Misaghi S, Fedorova A, Deshayes K, et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. JOURNAL OF CELL BIOLOGY. NEW YORK: ROCKEFELLER UNIV PRESS; 2009;187(1):61–70.
MLA
Lamkanfi, Mohamed, JL Mueller, AC Vitari, et al. “Glyburide Inhibits the Cryopyrin/Nalp3 Inflammasome.” JOURNAL OF CELL BIOLOGY 187.1 (2009): 61–70. Print.
@article{836549,
  abstract     = {Inflammasomes activate caspase-1 for processing and secretion of the cytokines interleukin-1 beta (IL-1 beta) 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-1 beta 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-1 beta secretion.},
  author       = {Lamkanfi, Mohamed and Mueller, JL and Vitari, AC and Misaghi, S and Fedorova, A and Deshayes, K and Lee, WP and Hoffman, HM and Dixit, VM},
  issn         = {0021-9525},
  journal      = {JOURNAL OF CELL BIOLOGY},
  language     = {eng},
  number       = {1},
  pages        = {61--70},
  publisher    = {ROCKEFELLER UNIV PRESS},
  title        = {Glyburide inhibits the Cryopyrin/Nalp3 inflammasome},
  url          = {http://dx.doi.org/10.1083/jcb.200903124},
  volume       = {187},
  year         = {2009},
}

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