Melatonin administration to wild-type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis

Ibtissem Rahim, Bahia Djerdjouri, Ramy K. Sayed, Marisol Fernández-Ortiz, Beatriz Fernández-Gil, Agustín Hidalgo-Gutiérrez, Luis C. López, Germaine Escames, Russel J. Reiter, Darío Acuña-Castroviejo

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

The NLRP3 inflammasome is involved in the innate immune response during inflammation. Moreover, melatonin blunts the NF-κB/NLRP3 connection during sepsis. Thus, we compared the roles of the NLRP3 inflammasome and/or melatonin treatment in the septic response of wild-type and NLRP3−/− mice. Mouse myocardial tissue was used for this purpose. The nuclear turnover of NF-κB was enhanced during sepsis, with an increase in TNFα, iNOS, and pro-IL-1β. The lack of inflammasome in NLRP3−/− mice significantly reduced that response and blunted IL-1β maturation due to the lack of caspase-1. Clock and Bmal1 did not change in both mouse strains, enhancing Chrono expression in mutants. RORα, which positively regulates Bmal1, was enhanced at a similar extend in both mouse strains, whereas the expression of the Bmal1 repressor, Rev–Erbα, increased in WT but was depressed in NLRP3−/− mice. Nampt, transcriptionally controlled by Bmal1, increased in WT mice together with Sirt1, whereas they remained unchanged in NLRP3−/− mice. Melatonin treatment reduced the septic response in a comparable manner as did the lack of NLRP3, but unlike the latter, it normalized the clock genes turnover through the induction of RORα and repression of Rev–Erbα and Per2, leading to enhanced Nampt and Sirt1. The lack of NLRP3 inflammasome converts sepsis to a moderate inflammatory disease and identifies NLRP3 as a main target for the treatment of sepsis. The efficacy of melatonin in counteracting the NLRP3 inflammasome activation further confirms the indoleamine as a useful therapeutic drug against this serious condition.

Original languageEnglish (US)
Article numbere12410
JournalJournal of pineal research
Volume63
Issue number1
DOIs
StatePublished - Aug 1 2017

Keywords

  • NF-κB
  • NLRP3 deficiency
  • NLRP3 inflammasome
  • heart
  • melatonin
  • sepsis

ASJC Scopus subject areas

  • Endocrinology

Fingerprint Dive into the research topics of 'Melatonin administration to wild-type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis'. Together they form a unique fingerprint.

Cite this