Document Type
Article
Presentation Date
12-4-2025
Abstract
In the context of neurodegeneration, activated microglia facilitate inflammation via secretion of TNF-α, IL-1α, and C1q. Astrocytes exposed to this signaling array polarize to a reactive inflammatory phenotype, termed A1 or A1-like. Astrocytes are essential for neuronal survival, synaptic support, and blood-brain barrier (BBB) function, but A1-like astrocytes upregulate inflammatory gene expression, downregulate neurotrophic factors, and secrete neurotoxic signals. The consequences of A1-like polarization on BBB function are unknown but may have etiological implications for some diseases. Frequently identified by upregulation of complement component 3 (C3), A1-like astrocytes have been characterized in neurodegenerative disorders like Alzheimer's disease, with polarization correlated with disease progression and severity. However, the role of A1-like astrocytes in neurodegeneration associated with chronic viral infections, like HIV-1-associated neurocognitive disorder (HAND), remains unclear. An in vitro system using primary human astrocytes, as well as a BBB model featuring primary human brain microvascular endothelial cells (BMECs) co-cultured with astrocytes, was used to elucidate cellular and molecular consequences of chronic astrocyte activation. As measured by whole transcriptome analysis and protein expression assays, repeated treatment with TNF-α, IL-1α, and C1q induced A1-like polarization of astrocytes both in monoculture and in a BBB model, resulting in increased secretion of pro-inflammatory signals. No substantial change to BBB permeability was observed. In contrast, exposure to HIV-1 viral protein Tat did not independently induce A1-like polarization. Ongoing investigations into the effect of astrocyte polarization on BBB integrity and treatment with pathogenic proteins may provide insights into the role of neurotoxic astrocytes in neurovirologic pathologies.
Recommended Citation
Lawrence, Jill M; Dampier, Will; Mell, Joshua Chang; De Souza, Diehl R; Schardien, Kayla; Yeakle, Kyle; Barnett, R Jordan; Sen, Bhaswati; Ahmed, Azad; Bouchard, Michael; Wigdahl, Brian; and Nonnemacher, Michael R, "Inflammatory Microglia Signals Drive A1-Like Polarization of Astrocytes Even in the Presence of HIV-1 Tat." (2025). Kimmel Cancer Center Papers, Presentations, and Grand Rounds. Paper 84.
https://jdc.jefferson.edu/kimmelgrandrounds/84
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Language
English
Comments
This article is the author's final published version in Molecular Neurobiology, Volume 63, Issue 1, December 2025, Article Number 251.
The published version is available at https://doi.org/10.1007/s12035-025-05409-z. Copyright © The Author(s) 2025.