Glyburide inhibits the Cryopyrin/Nalp3 inflammasome

TLDR

Inflammasomes activate caspase‑1 to secrete IL‑1β and IL‑18, with Cryopyrin/NALP3 a key component triggered by microbial ligands, DAMPs, and crystals, and its dysregulation implicated in gout, Alzheimer’s, and silicosis, making Nalp3 inhibitors therapeutically promising. Glyburide blocks Cryopyrin inflammasome activation independently of its cyclohexylurea‑mediated binding to ATP‑sensitive K⁺ channels, indicating inhibition occurs upstream of Cryopyrin. Glyburide and its analogues prevent Cryopyrin‑driven IL‑1β secretion, delay LPS‑induced lethality in mice, and represent the first compounds to inhibit Cryopyrin activation and microbial ligand‑, DAMP‑, and crystal‑induced IL‑1β release.

Abstract

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.