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.

Calmodulin inhibitor ameliorates cognitive dysfunction via inhibiting nitrosative stress and NLRP3 signaling in mice with bilateral carotid artery stenosis

“…Consistently, DY‐9836 preferentially inhibits protein tyrosine nitration and caspase‐1/IL‐1β signaling. Indeed, it was reported that peroxynitrite play a critical role in triggering NLRP3 inflammasome activation . Together with our observation, dual‐target modulators (low dose DY‐9836 + PSA) might particularly potent in inhibiting protein tyrosine nitration and subsequently lead to decreased NLRP3/caspase‐1/IL‐1β signaling, eventually attenuate the hypoperfusion‐induced CaMKII dephosphorylation and cognitive dysfunction.…”

Endothelial GPR124 Exaggerates the Pathogenesis of Atherosclerosis by Activating Inflammation

“…The macrophage content of the atherosclerotic vessel depends on the extent of the inflammatory reaction [41, 42]. Notably, several recent studies suggested that nitrosative stress is a key trigger of inflammasome activation [14, 43]. In the present study, an elevation in NLRP3 in the aortic sinus of atherosclerosis mice was observed, and a further dramatic increase was evidenced in atherosclerotic mice with GPR124 overexpression.…”

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

“…NLRP3 inflammasome dysregulation is linked to multiple neurodegenerative diseases (Gordon et al, ; Heneka et al, ; Song, Pei, Yao, Wu, & Shang, ), and drives neuroinflammation through caspase‐1 and IL‐1β activation. Caspase‐1 and IL‐1β have previously been identified as key pathogenic drivers of ALS (Friedlander, Brown, Gagliardini, Wang, & Yuan, ; Li et al, ; Meissner, Molawi, & Zychlinsky, ), and prior studies have demonstrated inflammasome activation and upregulation of NLRP3 in both human ALS, and SOD1 G93A rodent models (Bellezza et al, ; Debye et al, ; Gugliandolo, Giacoppo, Bramanti, & Mazzon, ; Johann et al, ), suggesting that the NLRP3 inflammasome could play a key role in ALS disease pathology. Surprisingly, however, a previous study showed that although SOD1 G93A activated caspase‐1 and produced mature IL‐1β in microglia, this occurred independently of NLRP3 inflammasomes (Meissner, Molawi, & Zychlinsky, ).…”

“…Microglial expression of NLRP3, and inflammasome component upregulation and activation is observed in Alzheimer's disease and Parkinson's disease (Gordon et al, ; Heneka et al, ). Inflammasome activation and upregulation of NLRP3 inflammasome components have also been observed in ALS patients and mouse models of ALS (Bellezza et al, ; Johann et al, ), with caspase‐1 and IL‐1β playing key roles in ALS pathology (Meissner, Molawi, & Zychlinsky, ). Despite this, a recent study suggested that microglia in SOD1 G93A mice, and human ALS patients do not express NLRP3 (Johann et al, ).…”

“…Inflammasome activation and upregulation of NLRP3 inflammasome components have also been observed in ALS patients and mouse models of ALS (Bellezza et al, 2018;Johann et al, 2015), with caspase-1 and IL-1β playing key roles in ALS pathology (Meissner, Molawi, & Zychlinsky, 2010). Despite this, a recent study suggested that microglia in SOD1 G93A mice, and human ALS patients do not express NLRP3 (Johann et al, 2015).…”