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

J Gerontol A Biol Sci Med Sci. 2020 Jul 13;75(8):1457-1464. doi: 10.1093/gerona/glz239.

Abstract

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.

Keywords: Aging; Autophagy; MCC950; NLRP3 inflammasome; PPARα.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Animals
  • Autophagy / drug effects*
  • Fatty Liver / prevention & control
  • Furans
  • Gene Expression
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Indenes
  • Inflammasomes / antagonists & inhibitors*
  • Lipids / blood
  • Liver / metabolism
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
  • PPAR alpha / drug effects*
  • Proto-Oncogene Proteins c-akt / drug effects
  • Sulfonamides
  • Sulfones / pharmacology*
  • TOR Serine-Threonine Kinases / drug effects

Substances

  • Furans
  • Heterocyclic Compounds, 4 or More Rings
  • Indenes
  • Inflammasomes
  • Lipids
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • PPAR alpha
  • Sulfonamides
  • Sulfones
  • N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases