Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice

FASEB J. 2015 Sep;29(9):3863-75. doi: 10.1096/fj.15-273656. Epub 2015 Jun 4.


We determined the NF-κB- and NOD-like receptor (NLR)P3-dependent molecular mechanisms involved in sepsis and evaluated the role of retinoid-related orphan receptor (ROR)-α in melatonin's anti-inflammatory actions. Western blot, RT-PCR, ELISA, and spectrophotometric analysis revealed that NF-κB and NLRP3 closely interact, leading to proinflammatory and pro-oxidant status in heart tissue of septic C57BL/6J mice. Moreover, mitochondrial oxygen consumption was reduced by 80% in septic mice. In vivo and in vitro analysis showed that melatonin administration blunts NF-κB transcriptional activity through a sirtuin1-dependent NF-κB deacetylation in septic mice. Melatonin also decreased NF-κB-dependent proinflammatory response and restored redox balance and mitochondrial homeostasis, thus inhibiting the NLRP3 inflammasome. In an important finding, the inhibition of NF-κB by melatonin, but not that of NLRP3, was blunted in RORα (sg/sg) mice, indicating that functional RORα transcription factor is necessary for the initiation of the innate immune response against inflammation. Our results are evidence of the NF-κB/NLRP3 connection during sepsis and identify NLRP3 as a novel molecular target for melatonin. The multiple molecular targets of melatonin in this study explain its potent anti-inflammatory efficacy against systemic innate immune activation and herald a promising therapeutic application for melatonin in the treatment of sepsis.

Keywords: bmal1; inflammasome; innate immunity; oxidative stress; sirtuin-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism*
  • Immunity, Innate / drug effects*
  • Immunity, Innate / genetics
  • Melatonin / pharmacology*
  • Mice
  • Mice, Transgenic
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / immunology
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism*
  • Oxidation-Reduction / drug effects
  • Sepsis / genetics
  • Sepsis / immunology
  • Sepsis / metabolism*
  • Sepsis / pathology


  • Carrier Proteins
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Rora protein, mouse
  • Melatonin