Linking brain inflammation to long-COVID and other neurological conditions
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To understand the connection between inflammation in the brain and long-COVID, LLNL researchers are studying two key inflammatory molecules, TNF-α and IL-6, which have been found in COVID-19 patients at higher concentrations.
Inflammation has long been linked to neurodegenerative diseases (e.g., Alzheimer’s) and psychiatric disorders (e.g., depression). More recently, long-COVID—a condition where symptoms persist long after the initial COVID-19 infection—has been associated with elevated levels of inflammation in the brain. People with long-COVID often report brain fog, memory problems, and difficulty concentrating, but scientists still don’t fully understand how inflammation might cause these issues.
In a recent study, published in Frontiers of Cellular Neuroscience, researchers at Lawrence Livermore National Laboratory (LLNL) studied the effects of two key inflammatory molecules, TNF-α and IL-6, on brain cells. They used a laboratory model that mimics human brain tissue, combining neurons (the cells responsible for transmitting signals in the brain) and astrocytes (additional brain cells that play a key role in maintaining brain health). This model was created using human stem cells that were reprogrammed to behave like the neurons and astrocytes found in the brain.
To study how prolonged exposure to the inflammatory molecules affect brain cell activity, the team exposed these brain cell cultures to different concentrations of TNF-α and IL-6, ranging from levels typically found in healthy individuals to much higher levels seen in patients with severe inflammation, such as those hospitalized with COVID-19 or experiencing long-COVID. They then measured how the cells’ electrical activity—essentially how brain cells communicate—changed over time.
At low concentrations, TNF-α increased brain activity, potentially fine-tuning brain function, but at higher concentrations, it caused significant reductions in activity, cell damage, and the release of additional inflammatory molecules. While IL-6 exposure led to a general reduction in brain cell activity, its effects were less pronounced than those of TNF-α. Additionally, IL-6 appeared to have some protective effects, reducing the toxic impact of high levels of TNF-α when the two molecules were present together. However, while IL-6 counteracted the effects of low TNF-α levels, at higher levels, TNF-α appeared to be too dominant for IL-6 to have any protective influence.
Overall, the study underscores the complexity of inflammation in the brain and opens the door to developing new strategies to protect brain health in conditions linked to chronic inflammation. The researchers note that their model does not include microglia, the brain’s immune cells, which are key players in neuroinflammation. Thus, future studies will need to investigate how microglia interact with TNF-α and IL-6 and whether they amplify or counteract the effects observed in this study.
This research was funded by LLNL’s Laboratory Directed Research and Development program (22-DR-007).
[Noah Goshi, Doris Lam, Chandrakumar Bogguri, Vivek George, Aimy Sebastian, Jose Cadena, Nicole Leon, Nicholas Hum, Dina Weilhammer, Nicholas Fischer, Heather Enright, Direct effects of prolonged TNF-α and IL-6 exposure on neural activity in human iPSC-derived neuron-astrocyte co-cultures, Frontiers in Cellular Neuroscience (2025), doi: 10.3389/fncel.2025.1512591.]
–Physical and Life Sciences Communications Team
