Stress granule assembly is a trigger for tumor necrosis factor alpha production in SH-SY5Y neuroblastoma cells

Tumor necrosis factor alpha (TNF-α) is a key pro-inflammatory cytokine that orchestrates innate immune responses to infections and other cellular stressors. Chronic inflammation causes persistent TNF-α overproduction, which promotes apoptosis and necroptosis. Excessive production of TNF-α contributes to neurodegeneration in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. Although anti-TNF-α antibodies are effective in treating autoimmune diseases such as rheumatoid arthritis, they cannot penetrate the brain and reduce TNF-α levels in neuronal cells. Here, we investigate the role of stress granule formation in regulating TNF-α production in human SH-SY5Y neuroblastoma cells. Stress granules are dynamic membraneless ribonucleoprotein complexes that assemble in response to various stress stimuli. They contain RNAs, RNA-binding proteins, and ribosomal components. In particular, the RNA-binding proteins TIA-1, TIAR, and FXR1, which negatively regulate TNF mRNA translation, are incorporated into stress granules under stress. Using immunocytochemistry, we show that FXR1 is progressively recruited to stress granules during sodium arsenite-induced stress in SH-SY5Y cells. Sequestration of FXR1 into stress granules disrupts its interaction with TNF mRNA, resulting in increased TNF-α production. Furthermore, pharmacological inhibition of stress granule assembly by the integrated stress response inhibitor (ISRIB) prevents stress-induced excessive TNF-α production in SH-SY5Y cells. Thus, our findings indicate that stress granule assembly triggers TNF-α production. Given that some known stress granule inhibitors can cross the blood–brain barrier, we propose that they may be promising agents for reducing the excessive neurotoxic production of TNF-α during neuroinflammation, provided that our findings are confirmed in other cell cultures and in vivo .