Garcia 2015 FASEB J

García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC, Acuña-Castroviejo D (2015) Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J 29:3863-75.

» PMID: 26045547

Garcia JA, Volt H, Venegas C, Doerrier C, Escames G, Lopez LC, Acuna-Castroviejo D (2015) FASEB J

Abstract: 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

• O2k-Network Lab: ES Granada Acuna-Castroviejo D

Labels: MiParea: Respiration, mtDNA;mt-genetics, Pharmacology;toxicology  Pathology: Sepsis 

Organism: Mouse  Tissue;cell: Heart  Preparation: Permeabilized tissue 

Coupling state: OXPHOS  Pathway: NS, ROX  HRR: Oxygraph-2k 

Melatonin