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Dissertation
Evaluating TLR4 and dopamine mediated inflammatory responses in human macrophages across distinct culture and serum conditions
Doctor of Philosophy (Ph.D.), Drexel University
Mar 2025
DOI:
https://doi.org/10.17918/00010910
Abstract
Macrophages are key innate immune cells that regulate essential inflammatory processes. As such, these cells are highly sensitive to stimuli from both endogenous and exogenous sources. Classically, toll-like receptor activation by bacterial products such as lipopolysaccharide (LPS) drives NF-kB mediated inflammation in human macrophages. Surprisingly, our data also indicate that the neurotransmitter dopamine can drive NF-kB mediated inflammation in these cells. LPS driven inflammation induces the production of inflammatory cytokines such as IL-1b and IL-6 from macrophages, which has also been noted in response to dopamine stimulation. Serum availability in vitro can alter macrophage inflammatory function. However, the mechanism by which serum alters NF-kB mediated inflammatory dynamics in the presence of LPS is understudied. Moreover, the mechanism(s) by which dopamine drives macrophage inflammation remain unclear. Our data show that dopamine mediated increases in IL-6 secretion correlated with the expression pattern of dopamine receptor transcripts, specifically the presence of D1-like receptors, and the lack of DRD3. Mechanistically, these effects are mediated by NF-kB nuclear translocation, which may be activated, at least in part, by Akt signaling. We also found that classical activation of NF-kB mediated inflammation via LPS is influenced by serum availability in vitro. Specifically, both bovine serum supplementation and culture in macrophage serum free media (M-SFM) significantly altered the baseline transcriptome of macrophages. Additionally, M-SFM culture significantly suppressed the NF-kB response to LPS while the impact of FBS supplementation on pharmacodynamics was related to the base media. Culture media and serum supplementation also drove morphological differences (area, length-to-width, perimeter-to-area ratio) in macrophages. Overall, these data provide more understanding of both classical (TLR4) and dopaminergic stimulation of macrophage inflammation, and the impact of the in vitro microenvironment on these processes during experimentation.
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Details
- Title
- Evaluating TLR4 and dopamine mediated inflammatory responses in human macrophages across distinct culture and serum conditions
- Creators
- Breana Brittney Channer-Ellis
- Contributors
- Peter J. Gaskill (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xii, 159 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 991022047521704721