NLRP3 Inflammasome Inhibition by MCC950 in Aged Mice Improves Health via Enhanced Autophagy and PPARα Activity

Rozalyn Anderson; Mario D. Cordero; Pedro Bullón; Jesús Ruiz-Cabello; Avril A B Robertson; Bernhard Ryffel; Antonio J Pérez-Pulido; Jordi Muntané; Mónica Pérez-Alegre; Eloísa Andújar-Pulido; Patricia de la Cruz; Matthew A Cooper; Debora Lendines-Cordero; Elísabet Alcocer-Gómez; Beatriz Castejón-Vega; Fabiola Marín-Aguilar

Resumen:

The NLRP3 inflammasome has emerged as an important regulator of metabolic disorders and age-related diseases in NLRP3-deficient mice. In this article, we determine whether, in old mice C57BL6J, the NLRP3 inflammasome inhibitor MCC950 is able to attenuate age-related metabolic syndrome to providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice. In addition, MCC950 inhibited the Pi3K/AKT/mTOR pathway, enhanced autophagy, and activated peroxisome proliferator-activated receptor-α in vivo and in vitro. The data suggest that MCC950 mediates the protective effects by the mammalian target of rapamycin inhibition, thus activating autophagy and peroxisome proliferator-activated receptor-α. In conclusion, pharmacological inhibition of NLRP3 in aged mice has a significant impact on health. Thus, NLRP3 may be a therapeutic target of human age-related metabolic syndrome.