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Dissertation
Characterizing pro-inflammatory A1-like astrocyte polarization in primary human cell models of chronic inflammation and HIV-1 Tat exposure
Doctor of Philosophy (Ph.D.), Drexel University
Aug 2024
DOI:
https://doi.org/10.17918/00010589
Abstract
Activated microglia secretion of TNF-[alpha], IL-1[alpha], and C1q during neuroinflammation induces polarization of astrocytes to a neurotoxic phenotype. These A1-like astrocytes transition from promoting neuronal survival and supporting blood-brain barrier (BBB) function, to secreting cytotoxic proteins and inflammatory mediators, including complement C3 and immune cell-attracting chemokines. While neuronal damage and death is a known consequence of A1- like astrocyte, less is understood about the effects on the BBB, which may have important etiological implications. A1-like astrocytes contribute to the pathology of neurodegenerative diseases as well as normal aging; however, their role in infectious disease has not been thoroughly investigated. Recently, several pathogenic proteins have been confirmed to independently induce A1-like polarization, a result that may prove relevant to chronic neuroviral infections like human immunodeficiency virus type 1 (HIV-1), in which proteins like HIV-1 Tat are constitutively expressed in the CNS. Given the difficulty of culturing adult human astrocytes, most research into A1-like astrocytes utilizes rodent cells or cell lines, methods that are not as representative as primary human cells. Here, we describe an in vitro model of A1-like polarization using primary human fetal astrocytes, as well as a coculture model of the BBB using primary human brain microvascular endothelial cells. With this model, we have characterized RNA and protein expression profiles, and identified inflammatory signaling patterns, in A1-like primary human astrocytes. While BBB-associated astrocytes can polarize to an A1-like phenotype, it does not ultimately compromise the integrity of the barrier. Interestingly, A1-like polarization was not induced by chronic exposure to the HIV-1 viral accessory protein Tat; however, unique effects did emerge following exposure to both Tat and simulated microglia signaling, representing the chronic neuroinflammation present in HIV-1. Further investigation may provide insights into the roles of A1-like astrocytes in HIV-1 and other neuroinfectious diseases.
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Details
- Title
- Characterizing pro-inflammatory A1-like astrocyte polarization in primary human cell models of chronic inflammation and HIV-1 Tat exposure
- Creators
- Jill M. Lawrence
- Contributors
- Michael R. Nonnemacher (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xiv, 235 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991021901610404721