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

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

  • J Pineal Res. 2017 Aug;63(1). doi: 10.1111/jpi.12410.
Ibtissem Rahim 1 2 3,  Bahia Djerdjouri 3,  Ramy K Sayed 1 4,  Marisol Fernández-Ortiz 1 5,  Beatriz Fernández-Gil 1 5,  Agustín Hidalgo-Gutiérrez 1 5,  Luis C López 1 5 6,  Germaine Escames 1 5 6,  Russel J Reiter 7,  Darío Acuña-Castroviejo 1 5 6
Affiliations

Affiliations

  • 1 Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.
  • 2 Département de Biologie et Physiologie Cellulaire, Faculté des Sciences de la Nature et de la Vie, Université Blida 1, Blida, Algeria.
  • 3 Faculté des Sciences Biologiques, Laboratoire de Biologie Cellulaire et Moléculaire, Université des Sciences et de la Technologie Houari Boumediene, Bab-Ezzouar, Algiers, Algeria.
  • 4 Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt.
  • 5 Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
  • 6 CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, Granada, Spain.
  • 7 Department of Cell Systems and Anatomy, UT Health, San Antonio, TX, USA.
PMID: 28370493 DOI: 10.1111/jpi.12410
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.

Keywords

NF-κB; NLRP3 deficiency; NLRP3 inflammasome; heart; melatonin; sepsis.

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