Direct effects of prolonged TNF-α and IL-6 exposure on neural activity in human iPSC-derived neuron-astrocyte co-cultures

Goshi, Noah; Lam, Doris; Bogguri, Chandrakumar; George, Vivek Kurien; Sebastian, Aimy; Cadena, Jose; Leon, Nicole F.; Hum, Nicholas R.; Weilhammer, Dina R.; Fischer, Nicholas O.; Enright, Heather A.

doi:10.3389/fncel.2025.1512591

Direct effects of prolonged TNF-α and IL-6 exposure on neural activity in human iPSC-derived neuron-astrocyte co-cultures

Journal Article · Wed Feb 12 00:00:00 EST 2025 · Frontiers in Cellular Neuroscience

DOI:https://doi.org/10.3389/fncel.2025.1512591· OSTI ID:2533621

Goshi, Noah ^[1]; Lam, Doris ^[1]; Bogguri, Chandrakumar ^[1]; George, Vivek Kurien ^[1]; Sebastian, Aimy ^[1]; Cadena, Jose ^[1]; Leon, Nicole F. ^[1]; Hum, Nicholas R. ^[1]; Weilhammer, Dina R. ^[1]; Fischer, Nicholas O. ^[1]; Enright, Heather A. ^[1]

Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Cognitive impairment is one of the many symptoms reported by individuals suffering from long-COVID and other post-viral infection disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A common factor among these conditions is a sustained immune response and increased levels of inflammatory cytokines. Tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are two such cytokines that are elevated in patients diagnosed with long-COVID and ME/CFS. In this study, we characterized the changes in neural functionality, secreted cytokine profiles, and gene expression in co-cultures of human iPSC-derived neurons and primary astrocytes in response to prolonged exposure to TNF-α and IL-6. We found that exposure to TNF-α produced both a concentration-independent and concentration-dependent response in neural activity. Burst duration was significantly reduced within a few days of exposure regardless of concentration (1 pg/mL – 100 ng/mL) but returned to baseline after 7 days. Treatment with low concentrations of TNF-α (e.g., 1 and 25 pg/mL) did not lead to changes in the secreted cytokine profile or gene expression but still resulted in significant changes to electrophysiological features such as interspike interval and burst duration. Conversely, treatment with high concentrations of TNF-α (e.g., 10 and 100 ng/mL) led to reduced spiking activity, which may be correlated to changes in neural health, gene expression, and increases in inflammatory cytokine secretion (e.g., IL-1β, IL-4, and CXCL-10) that were observed at higher TNF-α concentrations. Prolonged exposure to IL-6 led to changes in bursting features, with significant reduction in the number of spikes in bursts across a wide range of treatment concentrations (i.e., 1 pg/mL–10 ng/mL). In combination, the addition of IL-6 appears to counteract the changes to neural function induced by low concentrations of TNF-α, while at high concentrations of TNF-α the addition of IL-6 had little to no effect. Conversely, the changes to electrophysiological features induced by IL-6 were lost when the cultures were co-stimulated with TNF-α regardless of the concentration, suggesting that TNF-α may play a more pronounced role in altering neural function. These results indicate that increased concentrations of key inflammatory cytokines associated with long-COVID can directly impact neural function and may be a component of the cognitive impairment associated with long-COVID and other post-viral infection disorders.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE Laboratory Directed Research and Development (LDRD) Program; USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 2533621

Report Number(s):: LLNL--JRNL-2000692

Journal Information:: Frontiers in Cellular Neuroscience, Journal Name: Frontiers in Cellular Neuroscience Vol. 19; ISSN 1662-5102

Publisher:: Frontiers Media S.A.Copyright Statement

Country of Publication:: United States

Language:: English

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Atypical â€œseizure-likeâ€ activity in cortical reverberating networks in vitro can be caused by LPS-induced inflammation: a multi-electrode array study from a hundred neurons Gullo, Francesca; Amadeo, Alida; Donvito, Giulia Frontiers in Cellular Neuroscience, Vol. 8 https://doi.org/10.3389/fncel.2014.00361	journal	November 2014
TNF-Mediated Homeostatic Synaptic Plasticity: From in vitro to in vivo Models Heir, Renu; Stellwagen, David Frontiers in Cellular Neuroscience, Vol. 14 https://doi.org/10.3389/fncel.2020.565841	journal	September 2020
Spatiotemporal analysis of 3D human iPSC-derived neural networks using a 3D multi-electrode array Lam, Doris; Enright, Heather A.; Cadena, Jose Frontiers in Cellular Neuroscience, Vol. 17 https://doi.org/10.3389/fncel.2023.1287089	journal	November 2023
Biphasic response of human iPSC-derived neural network activity following exposure to a sarin-surrogate nerve agent Bogguri, Chandrakumar; George, Vivek Kurien; Amiri, Beheshta Frontiers in Cellular Neuroscience, Vol. 18 https://doi.org/10.3389/fncel.2024.1378579	journal	September 2024
Neural Coding With Bursts—Current State and Future Perspectives Zeldenrust, Fleur; Wadman, Wytse J.; Englitz, Bernhard Frontiers in Computational Neuroscience, Vol. 12 https://doi.org/10.3389/fncom.2018.00048	journal	July 2018
A Spike Train Distance Robust to Firing Rate Changes Based on the Earth Mover’s Distance Sihn, Duho; Kim, Sung-Phil Frontiers in Computational Neuroscience, Vol. 13 https://doi.org/10.3389/fncom.2019.00082	journal	December 2019
Development of Micro-Electrode Array Based Tests for Neurotoxicity: Assessment of Interlaboratory Reproducibility with Neuroactive Chemicals Novellino, A.; Scelfo, Bibiana; Palosaari, T. Frontiers in Neuroengineering, Vol. 4 https://doi.org/10.3389/fneng.2011.00004	journal	January 2011
Cerebrospinal Fluid and Microdialysis Cytokines in Severe Traumatic Brain Injury: A Scoping Systematic Review Zeiler, Frederick A.; Thelin, Eric Peter; Czosnyka, Marek Frontiers in Neurology, Vol. 8 https://doi.org/10.3389/fneur.2017.00331	journal	July 2017
Neurological manifestations of post-acute sequelae of COVID-19: which liquid biomarker should we use? Comeau, Dominique; Martin, Mykella; Robichaud, Gilles A. Frontiers in Neurology, Vol. 14 https://doi.org/10.3389/fneur.2023.1233192	journal	July 2023
Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures Lam, Doris; Sebastian, Aimy; Bogguri, Chandrakumar Frontiers in Toxicology, Vol. 4 https://doi.org/10.3389/ftox.2022.983415	journal	August 2022
The Regulatory Role of IL-10 in Neurodegenerative Diseases Porro, Chiara; Cianciulli, Antonia; Panaro, Maria Antonietta Biomolecules, Vol. 10, Issue 7 https://doi.org/10.3390/biom10071017	journal	July 2020
Implications of Innate Immunity in Post-Acute Sequelae of Non-Persistent Viral Infections Hirschenberger, Maximilian; Hunszinger, Victoria; Sparrer, Konstantin Maria Johannes Cells, Vol. 10, Issue 8 https://doi.org/10.3390/cells10082134	journal	August 2021
Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)—A Systemic Review and Comparison of Clinical Presentation and Symptomatology Wong, Timothy L.; Weitzer, Danielle J. Medicina, Vol. 57, Issue 5 https://doi.org/10.3390/medicina57050418	journal	April 2021
Interleukin 4-induced neuroprotection and regulation of microglia activation as a therapeutic approach in the MPTP model of Parkinson's disease Spittau, Björn Neural Regeneration Research, Vol. 12, Issue 9 https://doi.org/10.4103/1673-5374.215250	journal	January 2017
Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders Hong, Heeok; Kim, Byung Sun; Im, Heh-In International Neurourology Journal, Vol. 20, Issue Suppl 1 https://doi.org/10.5213/inj.1632604.302	journal	May 2016
Interleukin-6, a Major Cytokine in the Central Nervous System Erta, María; Quintana, Albert; Hidalgo, Juan International Journal of Biological Sciences, Vol. 8, Issue 9 https://doi.org/10.7150/ijbs.4679	journal	January 2012

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Biological and medical sciences
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human iPSC derived neurons
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