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

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

Author information

1
*Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, and Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain; and Unidad de Gestión Clínica de Laboratorios, Hospital Universitario San Cecilio, Granada, Spain.
2
*Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, and Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain; and Unidad de Gestión Clínica de Laboratorios, Hospital Universitario San Cecilio, Granada, Spain dacuna@ugr.es.

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

PMID:
26045547
DOI:
10.1096/fj.15-273656
[Indexed for MEDLINE]

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