Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson’s disease

Abstract

Wilson’s disease (WD) is an inherited disorder characterized by excessive accumulation of copper in the body, particularly in the liver and brain. In the central nervous system (CNS), extracellular copper accumulation triggers pathological microglial activation and subsequent neurotoxicity. Growing evidence suggests that levels of inflammatory cytokines are elevated in the brain of murine WD models. However, the mechanisms associated with copper deposition to neuroinflammation have not been completely elucidated. In this study, we investigated how the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome contributes to copper-mediated neuroinflammation in an animal model of WD. Elevated levels of interleukin-1β, interleukin-18, interleukin-6, and tumor necrosis factor-α were observed in the sera of WD patients and toxic milk (TX) mice. The protein levels of inflammasome adaptor molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), cleaved caspase-1, and interleukin-1β were upregulated in the brain regions of the TX mice. The NLRP3 inflammasome was activated in the TX mice brains. Furthermore, the activation of NLRP3 inflammasome was noted in primary microglia treated with CuCl2, accompanied by the increased levels of cleaved caspase-1, ASC, and interleukin-1β. Blocking NLRP3 inflammasome activation with siNlrp3 or MCC950 reduced interleukin-1β and interleukin-18 production, thereby effectively mitigating cognitive decline, locomotor behavior impairment, and neurodegeneration in TX mice. Overall, our study demonstrates the contribution of copper overload-mediated activation of NLRP3 inflammasome to progressive neuropathology in the CNS of a murine model of WD. Therefore, blockade of the NLRP3 inflammasome activation could be a potential therapeutic strategy for WD.

A susceptibility putative haplotype within NLRP3 inflammasome gene influences ischaemic stroke risk in the population of Punjab, India

“…Present abundantly in atheromatous lesions in stroke patients, it participates in plaque development, its stability and progression to ischaemia (Paramel Verghese et al, 2016). Therefore, suppression of NLRP3 inflammasome-induced IL-1β production has proved fruitful in managing the stroke volume, infarct size and post-ischaemic neuroinflammation (Dong et al, 2021). Punjab, but it does not defy the viewpoint that expression of genes vary according to different ethnicities (Huang et al, 2015); hence caution is urged in the interpretation of results.…”

“…Present abundantly in atheromatous lesions in stroke patients, it participates in plaque development, its stability and progression to ischaemia (Paramel Verghese et al., 2016). Therefore, suppression of NLRP3 inflammasome‐induced IL‐1β production has proved fruitful in managing the stroke volume, infarct size and post‐ischaemic neuro‐inflammation (Dong et al., 2021). Present study has clarified for the first time that relationship of IL‐1β secretion during NLRP3 inflammasome activation is genetically mediated, as five SNPs within NLRP3 gene in the form of putative haplotype GTGTA are associated with the increased concentrations of IL‐1β in IS patients having one copy, which further increases with carriage of two copies.…”

Imperatorin inhibits mitogen‐activated protein kinase and nuclear factor kappa‐B signaling pathways and alleviates neuroinflammation in ischemic stroke

“…However, excessive and persistent inflammatory response mediated by over‐activated microglia will release a large number of inflammatory mediators and neurotoxic substances 33 . Overloaded IL‐1β, IL‐6, and TNF‐α act on adjacent microglia to induce neuroinflammation and glia‐activated feedback loops which aggravates the production of neurotoxic molecules 34 . In addition, excessive NO inhibits mitochondrial cytochrome oxidase, which results in neuronal apoptosis 35 …”

Probable Reasons for Neuron Copper Deficiency in the Brain of Patients with Alzheimer’s Disease: The Complex Role of Amyloid

“…Notably, copper regulation of the NLRP3 inflammasome is only specific to macrophages [122]. Given that microglia are a type of macrophage, this mechanism may also be applied to them, as studies have previously confirmed [123].…”