Melatonin could help prevent sepsis, the leading cause of death in hospital ICUs
Sepsis is a serious disease that occurs when the body has an exaggerated immune response to a bacterial infection. It is the leading cause of death in hospital Intensive Care Units (ICUs), and at present there is still no specific treatment for it, since although it is a systemic inflammation, known anti-inflammatories are not effective.
Now, scientists from the University of Granada, belonging to Biosanitary Research Institute of Granada and the Center for Biomedical Research, have discovered that melatonin, a hormone found naturally in the body and also given as a medicine, could help prevent sepsis.
Their work has been published in FASEB Journal, the most cited journal in the area of Biology in the world, and will be presented this July at the FASEB Science Research Conference Melatonin Biology: Actions and Therapeutics, to be held in Lisbon (Portugal).
This study has made it possible to identify that the activation of the NLRP3 inflammasome "is required and necessary" for the systemic inflammatory response in sepsis and its extreme severity. Likewise, the UGR researchers have discovered the molecular targets of melatonin that support its high efficacy as an anti-inflammatory in the clinic, a condition that is currently being evaluated in a clinical trial in the laboratory.
The NLRP3 inflammasome is ultimately responsible for the maturation of pro-inflammatory cytokines (proteins that regulate cell function) which, like pro-IL-1beta, pro-IL-18 and pro-IL-33, are induced in the inactivated by NF-kB, the classic pathway of innate immunity.
The studies carried out by José Antonio García Santos, main author of this work, made it possible to identify the connection between the classic pathway of innate immunity, Nf-kB, and the complementary pathway, NLRP3.
The role of the NLRP3 inflammasome
“We have been able to identify that the activation of the NLRP3 inflammasome is required and necessary for the systemic inflammatory response in sepsis, since it is ultimately responsible for the maturation of pro-inflammatory cytokines that, like pro-IL-1beta, pro-IL- 18 and pro-IL-33, are inactively induced by NF-kB ”.
When activated by the NLRP3 inflammasome, these cytokines, especially IL-1beta, positively feed back to Nf-kB, thus amplifying the immune response, which conditions the exaggerated response of systemic inflammation in sepsis.
Once these pathways were defined, the scientists studied the mechanisms responsible for their activation in mice, and thanks to the participation of RORalpha, a nuclear melatonin receptor, in the inhibition of innate immunity, they were able to identify this receptor as the mechanism of the anti-inflammatory action of melatonin, which also stimulates mitochondrial bioenergetics, slowing the production of free radicals and inhibiting the NLRP3 inflammasome.
“With this study, we have demonstrated the basis of chronoinflammation as a fundamental mechanism that promotes the Nf-kB / NLRP3 connection and systemic inflammation in sepsis. The disruption of this connection by melatonin inactivates all the innate immunity pathways activated in sepsis, which makes it possible to recover from septic shock and multi-organ failure and significantly increase survival ”, points out García Santos.
Bibliographic reference:
García JA, Volt H, Venegas C, Doerrier C, Escames G, López LC, Acuña-Castroviejo D.
Disruption of the NF-kB / NLRP3 connection by melatonin requires retinoid-related orphan sigma receptor and blocks the septic response in mice. FASEB J 2015; Jun 4. pii: fj.15-273656.
PMID: 26045547. http://www.ncbi.nlm.nih.gov/pubmed/26045547