Inhibiting Nrf2 Expression Exacerbates Nlrp3 Inflammasome Activation and Dopamine Neuron Degeneration in Parkinson's Disease Models

Parkinson's disease（PD） is a movement disorder characterized by the progressive loss of dopamine neurons, which affects the quality of life of severe patients and brings an increasing economic burden to society. Microglia-mediated neuroinflammation drives disease progression and becomes a critical factor in neuronal degeneration. Recent studies have found that Nrf2 expression levels are reduced during aging and neurodegenerative diseases, but its regulatory mechanism on microglia-induced neuroinflammation has not been fully elucidated. We studied the regulatory mechanism of inhibiting Nrf2 expression in Parkinson's disease models through in vivo and in vitro experiments. 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 Parkinson's disease 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. Our research results show that inhibiting the expression of Nrf2 in a mouse model of Parkinson's disease reduces the body's antioxidant levels and HO-1 protein expression, aggravates the proliferation of microglia and astrocytes in mice, and triggers It inhibits the activation of NLRP3 inflammasome and the release of downstream inflammatory factors in microglia, exacerbating MPTP-induced damage to dopaminergic neurons and ultimately leading to aggravation of movement disorders in mice. At the cellular level, we found that knocking out Nrf2 expression aggravated LPS-induced activation of the NLRP3 inflammasome, ASC assembly, and the expression of downstream inflammatory factors in BV2 cells. Our results confirmed that reduced Nrf2 activity regulates oxidative stress and inflammatory responses by reducing the downstream antioxidant enzyme HO-1 and activating the NLRP3 inflammasome in microglia.