Peroxynitrite Activates the NLRP3 Inflammasome Cascade in SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis

被引：61

作者：

Bellezza, Ilaria ^{[1
]}

Grottelli, Silvia ^{[1
]}

Costanzi, Egidia ^{[1
]}

Scarpelli, Paolo ^{[1
]}

Pigna, Eva ^{[2
]}

Morozzi, Giulio ^{[1
]}

Mezzasoma, Letizia ^{[1
]}

Peirce, Matthew J. ^{[1
]}

Moresi, Viviana ^{[2
]}

Adamo, Sergio ^{[2
]}

Minelli, Alba ^{[1
]}

机构：

[1] Univ Perugia, Dept Expt Med, I-06132 Perugia, Italy

[2] Sapienza Univ Rome, Interuniv Inst Myol, DAHFMO Unit Histol & Med Embryol, Rome, Italy

来源：

MOLECULAR NEUROBIOLOGY | 2018年 / 55卷 / 03期

关键词：

NLRP3; Peroxynitrite; iNOS; NOX2; Caspase; 1; Il-1; ss; MOTOR-NEURON DEGENERATION; NF-KAPPA-B; P2X7; RECEPTOR; NADPH OXIDASE; NITRIC-OXIDE; SPINAL-CORD; ALS MICE; KEY ROLE; CELLS; MICROGLIA;

D O I：

10.1007/s12035-017-0502-x

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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-1 beta. 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-1 beta. By activating NF-kappa B, 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.

引用

页码：2350 / 2361

页数：12

共 44 条

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