title: Peroxynitrite Activates the NLRP3 Inflammasome Cascade in SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.
abstract: Neuroinflammation, characterized by the appearance of reactive microglial and astroglial cells, is one of the several pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a fast-progressing and fatal neurodegenerative disease. Cerebrospinal fluid and spinal cord of ALS patients and SOD1 mutant mice show high concentrations of IL-1β. This interleukin, expressed as an inactive precursor, undergoes a proteolytic maturation by caspase1, whose activation, in turn, depends on inflammasomes. Whether and how inflammasome is activated in ALS models is still to be clarified. The mechanism of inflammasome activation was studied in murine microglial cells overexpressing hSOD1(G93A) and verified in the spinal cord of hSOD1(G93A) mice. Murine microglial hSOD1(G93A) cells express all the inflammasome components and LPS activates caspase1 leading to an increase in the secretion of IL-1β. By activating NF-κB, LPS increases ROS and NO levels that spontaneously react to form peroxynitrite, thus leading to protein nitration. Reduction in peroxynitrite levels results in a decrease in caspase1 activity. Protein nitration and caspase1 activity are concomitantly increased in the spinal cord of pre-symptomatic SOD1(G93A) mice. Oxidative/nitrosative stress induces peroxynitrite formation that may be a key trigger of caspase1/inflammasome activation. Peroxynitrite formation may play a critical role in inflammasome activation and might be exploited as potential therapeutic target for ALS.
authors.affiliation: Department of Experimental Medicine, P.le Severi, University of Perugia, 06132, Perugia, Italy. ilaria.bellezza@unipg.it.
authors.forename: Ilaria
authors.identifier: http://orcid.org/0000-0002-8106-1600
authors.initials: I
authors.lastname: Bellezza
authors.affiliation: Department of Experimental Medicine, P.le Severi, University of Perugia, 06132, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Grottelli
authors.affiliation: Department of Experimental Medicine, P.le Severi, University of Perugia, 06132, Perugia, Italy.
authors.forename: Egidia
authors.initials: E
authors.lastname: Costanzi
authors.affiliation: Department of Experimental Medicine, P.le Severi, University of Perugia, 06132, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Scarpelli
authors.affiliation: DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Rome, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Pigna
authors.affiliation: Department of Experimental Medicine, P.le Severi, University of Perugia, 06132, Perugia, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Morozzi
authors.affiliation: Department of Experimental Medicine, P.le Severi, University of Perugia, 06132, Perugia, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Mezzasoma
authors.affiliation: Department of Experimental Medicine, P.le Severi, University of Perugia, 06132, Perugia, Italy.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Peirce
authors.affiliation: DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Moresi
authors.affiliation: DAHFMO Unit of Histology and Medical Embryology, Interuniversity Institute of Myology, Sapienza University of Rome, Rome, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Adamo
authors.affiliation: Department of Experimental Medicine, P.le Severi, University of Perugia, 06132, Perugia, Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: Minelli
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C000606290:SOD1 protein, human; D030421:Peroxynitrous Acid; D000072105:Superoxide Dismutase-1
keywords: Caspase 1; Il-1β; NLRP3; NOX2; Peroxynitrite; iNOS