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

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.

• Authors: José A García, Huayqui Volt, Carmen Venegas, Carolina Doerrier, Germaine Escames, Luis C López, Darío Acuña-Castroviejo
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 29 Issue 9 Pg. 3863-75 (Sep 2015) ISSN: 1530-6860 [Electronic] United States
• PMID: 26045547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• 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

Topics

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