Genipin inhibits NLRP3 and NLRC4 inflammasome activation via autophagy suppression

TLDR

Inflammasomes are cytoplasmic multiprotein complexes that activate caspase‑1 and mature IL‑1β, and while they defend against infection, their overactivation contributes to autoinflammatory diseases. Genipin suppresses NLRP3 and NLRC4 inflammasome activation by inhibiting IL‑1β production, caspase‑1 activation, and ASC oligomerization—effects mediated through autophagy inhibition and UCP2‑ROS signaling—and protects mice from LPS‑, alum‑, and flagellin‑induced inflammatory responses.

Abstract

Inflammasomes are cytoplasmic, multiprotein complexes that trigger caspase-1 activation and IL-1β maturation in response to diverse stimuli. Although inflammasomes play important roles in host defense against microbial infection, overactive inflammasomes are deleterious and lead to various autoinflammatory diseases. In the current study, we demonstrated that genipin inhibits the induction of IL-1β production and caspase-1 activation by NLRP3 and NLRC4 inflammasomes. Furthermore, genipin specifically prevented NLRP3-mediated, but not NLRC4-mediated, ASC oligomerization. Notably, genipin inhibited autophagy, leading to NLRP3 and NLRC4 inflammasome inhibition. UCP2-ROS signaling may be involved in inflammasome suppression by genipin. In vivo, we showed that genipin inhibited NLRP3-dependent IL-1β production and neutrophil flux in LPS- and alum-induced murine peritonitis. Additionally, genipin provided protection against flagellin-induced lung inflammation by reducing IL-1β production and neutrophil recruitment. Collectively, our results revealed a novel role in inhibition of inflammatory diseases for genipin that has been used as therapeutics for centuries in herb medicine.