DOI
https://doi.org/10.25772/XHV3-2067
Defense Date
2018
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Biochemistry
First Advisor
Tomasz Kordula
Abstract
Neuroinflammation is hallmark of almost all central nervous system diseases. Along with infiltrating immune cells, resident glial cells of the central nervous system play a critical role in modulating inflammation and thus regulating disease severity. The NF-kB family of transcription factors are major transcriptional regulators of inflammation. RelA (p65) is the most well studied NF-kB family member; it has been well established that p65 functions to increase cytokine transcription in a variety of disease models. However, other NF-kB family members, namely RelB, have not been studied extensively as regulators of neuroinflammation. This report describes the both the function of RelB in glial cells during sterile neuroinflammation and during auto-immune neurological diseases such as multiple sclerosis. In the first part of this project we focused on studying astrocytes, as these glial cells are key regulators of homeostasis in the brain. We have established that primary human astrocytes exposed to pro-inflammatory cytokines such as IL-1 develop days-long “cytokine-tolerance” to subsequent cytokine activation. This adaptive component provides “memory” or “imprinting” of astrocytes, which resembles endotoxin-induced tolerance observed in macrophages. Mechanistically, we found that “cytokine-tolerance” in astrocytes depends on RelB. Although IL-1 initially activates the classical NF-kB protein p65, it subsequently induces RelB expression. Upon re-exposure to IL-1, the excess of RelB containing complexes occupy NF-kB binding sites on DNA diminish further expression of cytokines, and therefore limit inflammatory responses. We further confirmed our findings in an LPS-induced model of neuroinflammation, demonstrating that astrocytic RelB knockout results in increased cytokine expression in the brain. In the second part of this project, we investigated the role of glial cell derived RelB in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. In contrast to the LPS- induced model of neuroinflammation, astrocytic RelB had no effect on disease severity. However, we discovered oligodendrocyte-derived RelB functions to increase disease severity possibly by increasing cell death. These two projects demonstrate the crucial functions of glial cell derived RelB in regulating neuroinflammatory diseases.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
1-26-2018