Nrf2 Deficiency Exacerbates Parkinson's Disease by Aggravating NLRP3 Inflammasome Activation in MPTP-Induced Mouse
Ranran Lu1,2, Xu Zhou1,2, Lijie Zhang3
1Department of Neurology, The Second Affiliated Hospital of Xinjiang Medical University, Ürümqi, Xinjiang, People's Republic of China.
Background:
Parkinson's disease (PD) is a movement disorder characterized by the progressive loss of dopamine neurons. Microglia-mediated neuroinflammation drives disease progression and becomes a critical factor in neuronal degeneration. Recent studies have found that nuclear factor-erythroid 2-related-2 (Nrf2) expression levels are reduced during aging and neurodegenerative diseases, but its regulatory mechanism on microglia-induced neuroinflammation has not been fully elucidated.
Methods:
In vivo, we used the intraperitoneal injection of the neurotoxic drug neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to establish an animal model of PD and, at the same time, administered Nrf2 inhibitors ML385 and dimethyl fumarate to regulate Nrf2 protein levels. In vitro, we used si-RNA to knock out the Nrf2 gene to intervene in BV2 cells and used lipopolysaccharide (LPS) to stimulate and induce the cell model.
Results:
The study found that inhibition of Nrf2 expression aggravated the motor defects of PD mice, accompanied by a significant loss of dopaminergic neurons in the substantia nigra and striatum of the brain. In addition, after inhibition of Nrf2, the malondialdehyde (MDA) level in the substantia nigra of the midbrain of mice increased, and the levels of superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) decreased, accompanied by the proliferation of microglia and astrocytes. In addition, the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, the assembly of apoptosis-associated speck-like protein containing a CARD (ASC) protein in microglia, and the release of downstream inflammatory factors caspase-1 and interleukin (IL)-1β, were aggravated. At the cellular level, it was found that knocking out the expression of Nrf2 would aggravate the activation of NLRP3 inflammasomes and the assembly of ASC in LPS-induced BV2 cells.
Conclusion:
Inhibited Nrf2 activity can reduce the downstream antioxidant enzyme HO-1 and antioxidant levels, induce NLRP3 inflammasome activation and ASC protein assembly in microglia, and ultimately aggravate PD inflammatory response and dopamine neuron degeneration.
Insights
Inhibiting nuclear factor-erythroid 2-related-2 (Nrf2) worsens Parkinson's disease by increasing neuroinflammation and dopamine neuron loss. Reduced Nrf2 activity exacerbates oxidative stress and inflammasome activation, driving disease progression.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Parkinson's disease (PD) involves dopamine neuron loss and microglia-mediated neuroinflammation.
- Reduced nuclear factor-erythroid 2-related-2 (Nrf2) is observed in neurodegeneration, but its role in microglia-induced neuroinflammation is unclear.
Purpose of the Study:
- To investigate the regulatory mechanism of Nrf2 on microglia-induced neuroinflammation in Parkinson's disease.
- To elucidate how Nrf2 influences neuroinflammation and dopamine neuron degeneration.
Main Methods:
- Established a PD mouse model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and modulated Nrf2 levels with inhibitors (ML385, dimethyl fumarate).
- Utilized si-RNA to knock out Nrf2 in BV2 microglia cells and stimulated them with lipopolysaccharide (LPS).
Main Results:
- Nrf2 inhibition aggravated motor deficits, dopaminergic neuron loss, and oxidative stress (increased MDA, decreased SOD, HO-1) in PD mice.
- Inhibition of Nrf2 promoted microglial and astrocyte proliferation, activated the NLRP3 inflammasome, ASC protein assembly, and IL-1β release.
- Knocking out Nrf2 in BV2 cells exacerbated LPS-induced NLRP3 inflammasome activation and ASC assembly.
Conclusions:
- Inhibiting Nrf2 activity reduces antioxidant enzyme HO-1 and antioxidant levels.
- Nrf2 inhibition induces NLRP3 inflammasome activation and ASC protein assembly in microglia.
- These effects ultimately aggravate PD inflammatory response and dopamine neuron degeneration.
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