Compound C Inhibits NLRP3 Inflammasome through an AMPK-Independent Mechanism

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It has been demonstrated that NLRP3 inflammasome is a key contributor to obesity-related insulin resistance and type 2 diabetes (T2D), which are characterized with chronic, low-grade inflammation. Adenosine monophosphate-activated protein kinase (AMPK) is a principle intracellular energy sensor, which prevents the production of proinflammatory cytokines and has beneficial effects on the protection against T2D. Comound C, an inhibitor of AMPK, has been demonstrated to be not only an inhibitor of AMPK, but also has some actions independent of AMPK inhibition. We unexpectedly found 25uM compound C considerably inhibited IL-1βand IL-18 secretion when THP-1 cells were stimulated with 100ng/ml LPS plus 0.5mM palmitic acid (PA) (P < 0.01). In order to address the underlying mechanism, we examined whether compound C affected NLRP3 inflammasome, a multiprotein complex which controls the processing and production of IL-1β and IL-18. Contrary to our expectations, compound C significantly inhibited NLRP3 inflammasome activation (P < 0.05). Additionally, this effect was reproduced in AMPK siRNA transfected THP-1 cells, indicating that compound C exerts this function through an AMPK-independent mechanism. Mechanistically, we found compound C significantly suppresses mitochondria generated reactive oxygen species (ROS), which is required for NLRP3 inflammasome activation. In conclusion, we demonstrate for the first time that, compound C significantly inhibited NLRP3 inflammasome in an AMPK-independent manner, suggesting NLRP3 inflammasome is to be the novel target of compound C. And we inferred that compound C inhibit NLRP3 inflammasome may through the suppression of mitochondrial ROS production. These findings offer unique insight into compound C as a novel pharmacological agent with significant therapeutic potential in NLRP3 inflammasome-related disorders including obesity, insulin resistance and T2D. Further studies are needed to identify the effect of compound C on these diseases in vitro. Disclosure F. Wang: None. W. Yang: None. L. Wang: None. Y. Liu: None. Z. Mo: None.