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Glyburide inhibits the Cryopyrin/Nalp3 inflammasome

¹ Department of Physiological Chemistry, ² Department of Protein Engineering, and ³ Department of Immunology, Genentech, South San Francisco, CA 94080
⁴ Division of Rheumatology, Allergy, and Immunology, ⁵ Department of Pediatrics, and ⁶ Ludwig Institute of Cancer Research, School of Medicine, University of California, San Diego, La Jolla, CA 92093

Correspondence to Vishva M. Dixit: Dixit.vishva{at}gene.com

Inflammasomes activate caspase-1 for processing and secretion of the cytokines interleukin-1β (IL-1β) 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-1β 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-1β secretion.

Abbreviations used in this paper: ABC, ATP-binding cassette; BMDM, bone marrow–derived macrophage; DAMP, danger-associated molecular pattern; FCAS, familial cold-associated autoinflammatory syndrome; IL, interleukin; K_ATP, ATP-sensitive K⁺; LPS, lipopolysaccharide; PAMP, pathogen-associated molecular pattern; PBMC, peripheral blood mononuclear cell; SUR, sulfonylurea receptor.

© 2009 Lamkanfi et al.
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This article has been cited by other articles:

• Lamkanfi, M., Mueller, J. L., Vitari, A. C., Misaghi, S., Fedorova, A., Deshayes, K., Lee, W. P., Hoffman, H. M., Dixit, V. M. (2009). Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. JEM 206: i25-i25 [Full Text]  

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