| First Author | García JA | Year | 2015 |
| Journal | FASEB J | Volume | 29 |
| Issue | 9 | Pages | 3863-75 |
| PubMed ID | 26045547 | Mgi Jnum | J:225527 |
| Mgi Id | MGI:5693470 | Doi | 10.1096/fj.15-273656 |
| Citation | Garcia JA, et al. (2015) Disruption of the NF-kappaB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-alpha and blocks the septic response in mice. FASEB J 29(9):3863-75 |
| abstractText | We determined the NF-kappaB- and NOD-like receptor (NLR)P3-dependent molecular mechanisms involved in sepsis and evaluated the role of retinoid-related orphan receptor (ROR)-alpha in melatonin's anti-inflammatory actions. Western blot, RT-PCR, ELISA, and spectrophotometric analysis revealed that NF-kappaB 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-kappaB transcriptional activity through a sirtuin1-dependent NF-kappaB deacetylation in septic mice. Melatonin also decreased NF-kappaB-dependent proinflammatory response and restored redox balance and mitochondrial homeostasis, thus inhibiting the NLRP3 inflammasome. In an important finding, the inhibition of NF-kappaB by melatonin, but not that of NLRP3, was blunted in RORalpha (sg/sg) mice, indicating that functional RORalpha transcription factor is necessary for the initiation of the innate immune response against inflammation. Our results are evidence of the NF-kappaB/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.-Garcia, J. A., Volt, H., Venegas, C., Doerrier, C., Escames, G., Lopez., L. C., Acuna-Castroviejo, D. Disruption of the NF-kappaB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-alpha and blocks the septic response in mice. |
