Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy

Abstract

Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with Valosin Containing Protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones and brain. In this report, we demonstrate: (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, Caspase 1, IL-1β and IL-18 in the quadriceps muscles of VCPR155H/+ heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β(+)F4/80(+)Ly6C(+) inflammatory macrophages that infiltrate the muscles of VCPR155H/+ mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β (+)F4/80(+)Ly6C(+) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; (v) treatment of VCPR155H/+ mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80(+)Ly6C(+)IL-1β (+) macrophage infiltrates in the muscle and significantly ameliorated muscle strength. Together, these results suggest: (i) NLRP3 inflammasome and local IL-1β (+)F4/80(+)Ly6C(+) inflammatory macrophages contribute to pathogenesis of VCP-associated myopathy; and (ii) identified MCC950 specific inhibitor of the NLRP3 inflammasome with promising therapeutic potential for the treatment of VCP-associated myopathy.

Protection of Mcc950 against high-glucose-induced human retinal endothelial cell dysfunction

“… 37 , 38 Mcc950 not only inhibited NLRP3 inflammasome activation as evidenced by suppressing cleavage of caspase 1 and downstream interleukin IL-1 β production, but decreased apoptosis and mature IL-1 β released by HRECs. Thus, Mcc950 has an anti-inflammatory role in the pathogenesis of impaired glucose-mediated retinopathy, and these data agree with previous reports that Mcc950 can inhibit NLRP3 inflammasome activation in dermal and pulmonary inflammation, 31 crystal-induced kidney fibrosis, 33 valosin-containing protein-associated diseases, 32 cryopyrin-associated periodic syndromes, 20 , 39 , 40 hypertension, 41 and myocardial infarction. 42 …”

“…Activation of the NLRP3 inflammasome is thought to be key for the progression of pro-inflammatory effects of retinopathy including age-related macular degeneration 18 and DR. 27 Using immunofluorescence and western blot we confirmed NLRP3 inflammasome activation in human REC of proliferative membranes, a crucial characteristic of PDR. 28 , 29 , 30 The anti-NLRP3 inflammasome effect of Mcc950 for macrophages, microglia, myoblasts and dendritic cells is well described, 31 , 32 , 33 , 34 but its effect on inflammation of HRECs is unexplored. Thus, we investigated the potency of Mcc950 for attenuating inflammation in HRECs induced by high glucose.…”

The Overlapping Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

“…Recent mouse models of VCP showed that activation of the NLRP3 inflammasome is associated with VCP protein myopathy. Nalbandian et al (2017) reported a significant increase in the expression of NLRP3, Caspase 1, IL-1β, and IL-18 in the quadriceps of 12 and 24 months old VCPR155H/+heterozygous mice. Furthermore, a significant increase of IL-1β(+)F4/80(+)Ly6C(+) macrophages in the quadriceps and bones of the same mice were also observed and is positively correlated with high expression levels of TDP-43 and p62/SQSTM1 markers of VCP pathology and progressive muscle wasting (Nalbandian et al, 2017).…”

Anti-inflammatory and Anti-oxidant Activity of Hidrox® in Rotenone-Induced Parkinson’s Disease in Mice

“…Over the past two decades, inflammation in PD has received great interest by many researchers, highlighting microglial activation, cytokine production and oxidative damage in the in vivo model and post-mortem [ 4 , 5 ]. Therefore, neuroinflammation represents a key role in the progressive degeneration of dopaminergic neurons and in the pathogenesis of PD [ 6 , 7 ]. This is demonstrated by the discovery of high levels of some proinflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and many others, in the samples of the brain parenchyma and cerebrospinal fluid of affected patients from PD compared to control samples [ 8 ].…”