Abstract
Celastrol exhibits potential anti-inflammatory activity in a variety of inflammatory diseases, but the mechanism remains poorly understood. Activation of NLRP3 inflammasome is involved in multiple inflammatory diseases. Here, we show that celastrol abolishes the NLRP3 inflammasome activation, inhibits subsequent caspase-1 activation and IL-1β secretion both in vitro and in vivo. Notably, interruption of ASC oligomerization and autophagy activation are involved in NLRP3 inflammasome inactivation by celastrol. Importantly, in vivo results indicate that celastrol attenuates NLRP3 inflammasome-dependent inflammation diseases via autophagy-related pathway. Our results thus reveal celastrol as an inhibitor of NLRP3 inflammasome, implying the potential for clinical use of celastrol in treatment of NLRP3 inflammasome-driven inflammatory diseases.
Highlights
Celastrol, a natural triterpene, is an active ingredient isolated from the root bark of the traditional Chinese medicinal plant Tripterygium wilfordii Hook F [1]
We found that the effects of celastrol on NLRP3 inflammasome were significantly compromised in Caspase-1-/- mice, providing that the effect of celastrol on NLRP3 inflammasome activation depends on Caspase-1 (Supplementary Figure 1B-1D)
We show that a new anti-inflammation mechanism for celastrol carrying reducing IL-1β secretion via autophagy-mediated NLRP3 inflammasome inhibition
Summary
A natural triterpene, is an active ingredient isolated from the root bark of the traditional Chinese medicinal plant Tripterygium wilfordii Hook F (thunder god vine) [1]. Celastrol has potent antitumor activities, which include proliferation inhibition, apoptosis induction, invasion and angiogenesis suppression [2,3,4,5,6,7]. Liu et al have reported that celastrol ameliorates obesity via increasing leptin sensitivity [8]. Celastrol exhibits potent anti-inflammatory activities in various experimental models [9]. Celastrol inhibits cytokine expression by interrupting NF-κB signaling pathway [10]. Celastrol exhibits multiple beneficial effects on autoimmune diseases, including acute and chronic inflammation, neurodegenerative diseases [11,12,13]. The use of celastrol for treatment of inflammatory disorders is promising, the anti-inflammatory mechanism of celastrol are not fully understood
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