Dimethyl itaconate reprograms neurotoxic to neuroprotective primary astrocytes through the regulation of NLRP3 inflammasome and NRF2/HO-1 pathways

• Published in: Molecular and cellular neuroscience 2022-09, Vol.122, p.103758-103758, Article 103758
• Main Authors: Darvish Khadem, Mohammad, Tabandeh, Mohammad Reza, Haschemi, Arvand, Kheirollah, Alireza, Shahriari, Ali
• Format: Article
• Language: English
• Subjects: Apoptosis; Astrocyte; Immunometabolite; Inflammation; Itaconate; Oxidative stress
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2022.103758

The activation of neurotoxic reactive astrocytes contributes to the pathogenesis of many neurodegenerative diseases. Itaconate, a product of cellular metabolism, is released from activated macrophage/microglia and has been shown to regulate inflammatory responses in several mammalian cells. This study was designed to investigate the impact of cell-permeable dimethyl itaconate (DI) on reactive astrocyte-dependent neurotoxicity. Primary murine astrocyte cells were isolated and stimulated with lipopolysaccharide (LPS) to generate reactive astrocytes. Treating these activated cells with DI was able to diminish the neurotoxic phenotype of reactive astrocytes, as we found reduced LPS-induced Nod-like receptor protein 3 (NLRP3) inflammasome activation and interleukin-1β (IL-1β) secretion. DI reduced the level of inflammasome components, attenuated inflammasome assembly and subsequently reduced caspase-1 cleavage and IL-1β levels. Additionally, DI attenuated nuclear factor-kappa B (NF-κB) phosphorylation in LPS-activated astrocytes and also protected astrocytes from LPS-induced cytotoxicity, including a lowering of Bax and caspase3. DI-treated reactive astrocytes showed an elevated GSH/GSSG ratio and improved antioxidant defense factors including catalase and superoxide dismutase, while lipid peroxidation was reduced. We found that DI activated the nuclear factor 2 (NRF2) and heme oxygenase-1 (HO-1) pathway in astrocytes and thereby potentially control redox-regulation and the inflammatory state of astrocytes. Collectively, these results indicate the neuroprotective role of DI by reprogramming astrocytes from neurotoxic A1 to neuroprotective A2 states and thereby reveal a novel potential strategy for the treatment of neurodegenerative diseases. •Dimethyl itaconate (DI) alters the astrocyte phenotype from A1 neurotoxic to A2 neuroprotective.•DI modulates NLRP3/NF-κB inflammatory responses in reactive astrocyte cells via NRF2 activation.•DI attenuates the intrinsic apoptotic pathway and rescues astrocytes from cytotoxicity.•DI improves redox homeostasis of neurotoxic astrocyte cells through NRF2/HO-1 activation.