title: Melatonin administration to wild-type mice and nontreated NLRP3 mutant mice share similar inhibition of the inflammatory response during sepsis.
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.
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Département de Biologie et Physiologie Cellulaire, Faculté des Sciences de la Nature et de la Vie, Université Blida 1, Blida, Algeria.|Faculté des Sciences Biologiques, Laboratoire de Biologie Cellulaire et Moléculaire, Université des Sciences et de la Technologie Houari Boumediene, Bab-Ezzouar, Algiers, Algeria.
authors.forename: Ibtissem
authors.initials: I
authors.lastname: Rahim
authors.affiliation: Faculté des Sciences Biologiques, Laboratoire de Biologie Cellulaire et Moléculaire, Université des Sciences et de la Technologie Houari Boumediene, Bab-Ezzouar, Algiers, Algeria.
authors.forename: Bahia
authors.initials: B
authors.lastname: Djerdjouri
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt.
authors.forename: Ramy K
authors.initials: RK
authors.lastname: Sayed
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
authors.forename: Marisol
authors.initials: M
authors.lastname: Fernández-Ortiz
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Fernández-Gil
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Hidalgo-Gutiérrez
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.|CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, Granada, Spain.
authors.forename: Luis C
authors.initials: LC
authors.lastname: López
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.|CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, Granada, Spain.
authors.forename: Germaine
authors.identifier: http://orcid.org/0000-0003-1256-7656
authors.initials: G
authors.lastname: Escames
authors.affiliation: Department of Cell Systems and Anatomy, UT Health, San Antonio, TX, USA.
authors.forename: Russel J
authors.initials: RJ
authors.lastname: Reiter
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain.|CIBERfes, Ibs.Granada, and UGC de Laboratorios Clínicos, Complejo Hospitalario de Granada, Granada, Spain.
authors.forename: Darío
authors.identifier: http://orcid.org/0000-0002-9680-1560
authors.initials: D
authors.lastname: Acuña-Castroviejo
mesh_terms: D000818:Animals; D005260:Female; D006321:Heart / Q000187:drug effects; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D008550:Melatonin
keywords: NF-κB; NLRP3 deficiency; NLRP3 inflammasome; heart; melatonin; sepsis