title: Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin.
abstract: The connection between the innate immune system, clock genes, and mitochondrial bioenergetics was analyzed during aging and sepsis in mouse heart. Our results suggest that the sole NF-κB activation does not explain the inflammatory process underlying aging; the former also triggers the NLRP3 inflammasome that enhances caspase-1-dependent maturation of IL-1β. In this way, aged mice enter into a vicious cycle as IL-1β further activates the NF-κB/NLRP3 inflammasome link. The origin of NF-κB activation was related to the age-dependent Bmal1/Clock/RORα/Rev-Erbα loop disruption, which lowers NAD(+) levels, reducing the SIRT1 deacetylase ability to inactivate NF-κB. Consequently, NF-κB binding to DNA increases, raising the formation of proinflammatory mediators and inducing mitochondrial impairment. The cycle is then closed with the subsequent NLRP3 inflammasome activation. This paired contribution of the innate immune pathways serves as a catalyst to magnify the response to sepsis in aged compared with young mice. Melatonin administration blunted the septic response, reducing inflammation and oxidative stress, and enhancing mitochondrial function at the levels of nonseptic aged mice, but it did not counteract the age-related inflammation. Together, our results suggest that, although with different strengths, chronoinflammaging constitutes the biochemical substrate of aging and sepsis, and identifies the NLRP3 inflammasome as a new molecular target for melatonin, providing a rationale for its use in NLRP3-dependent diseases.
authors.affiliation: 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: Huayqui
authors.initials: H
authors.lastname: Volt
authors.affiliation: 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: José A
authors.initials: JA
authors.lastname: García
authors.affiliation: 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: Carolina
authors.initials: C
authors.lastname: Doerrier
authors.affiliation: 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: María E
authors.initials: ME
authors.lastname: Díaz-Casado
authors.affiliation: 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: Ana
authors.initials: A
authors.lastname: Guerra-Librero
authors.affiliation: 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: Luis C
authors.initials: LC
authors.lastname: López
authors.affiliation: 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: Germaine
authors.initials: G
authors.lastname: Escames
authors.affiliation: Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Jesús A
authors.initials: JA
authors.lastname: Tresguerres
authors.affiliation: 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.|Unidad de Gestión Clínica de Laboratorios, Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: Darío
authors.initials: D
authors.lastname: Acuña-Castroviejo
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects*; D058847:Inflammasomes / Q000378:metabolism*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D008550:Melatonin
keywords: NF-κB; NLRP3 inflammasome; clock genes; inflammaging; melatonin; mitochondria