Department of Basic Sciences, Division of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz 61357-831351, Iran.
Department of Basic Sciences, Division of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz 61357-831351, Iran; Stem Cells and Transgenic Technology Research Center, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
Mol Cell Neurosci. 2022 Sep;122:103758. doi: 10.1016/j.mcn.2022.103758. Epub 2022 Jul 20.
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.
细胞毒性反应性星形胶质细胞的激活有助于许多神经退行性疾病的发病机制。衣康酸是细胞代谢的产物，从激活的巨噬细胞/小胶质细胞中释放出来，并已被证明可调节几种哺乳动物细胞的炎症反应。本研究旨在研究细胞通透性二甲基衣康酸（DI）对反应性星形胶质细胞依赖性神经毒性的影响。分离原代鼠星形胶质细胞并用脂多糖（LPS）刺激以产生反应性星形胶质细胞。用 DI 处理这些激活的细胞能够减弱反应性星形胶质细胞的神经毒性表型，因为我们发现 LPS 诱导的 Nod 样受体蛋白 3（NLRP3）炎性小体激活和白细胞介素 1β（IL-1β）分泌减少。DI 降低了炎性小体成分的水平，减弱了炎性小体的组装，随后减少了半胱天冬酶-1 的切割和 IL-1β水平。此外，DI 减弱了 LPS 激活的星形胶质细胞中核因子-κB（NF-κB）的磷酸化，并且还保护星形胶质细胞免受 LPS 诱导的细胞毒性，包括 Bax 和半胱天冬酶 3 的降低。DI 处理的反应性星形胶质细胞表现出升高的 GSH/GSSG 比和改善的抗氧化防御因子，包括过氧化氢酶和超氧化物歧化酶，同时降低了脂质过氧化作用。我们发现 DI 在星形胶质细胞中激活了核因子 2（NRF2）和血红素加氧酶-1（HO-1）途径，从而可能控制星形胶质细胞的氧化还原调节和炎症状态。总之，这些结果表明 DI 通过将星形胶质细胞从神经毒性 A1 状态重编程为神经保护 A2 状态，从而发挥神经保护作用，揭示了一种治疗神经退行性疾病的新的潜在策略。
