Thesis
Altering metabolism repolarizes pro-inflammatory human macrophages
Master of Science (M.S.), Drexel University
Jun 2020
DOI:
https://doi.org/10.17918/00000038
Abstract
Macrophages, the primary innate immune cells of the body, regulate wound healing by switching between M1 and M2 phenotypes in order to kill bacteria, clear apoptotic cell debris, stimulate angiogenesis, and deposit functional extracellular matrix. However, a number of pathologies are characterized by macrophages that are stalled in a M1 state, and there is a need for biomaterials that can decrease M1 macrophage behavior. Previous research found that administration of unsaturated fatty acids, glycolysis inhibitors, and glutamate metabolism inhibitors decrease inflammatory gene and protein expression. Also, it has been shown that M1 macrophages primarily rely on glycolysis for energy, while M2 macrophages rely on oxidative phosphorylation. Because of this, the objective for this study was to design a metabolism-altering biomaterial to decrease M1 macrophage behavior. This was done in two phases, which were designing experiments to find the optimal combination of 6-Diazo-5-oxo-L-norleucine (DON), Quercetin (Que), and Docosahexaenoic acid (DHA) to decrease M1 behavior and creating a liposome drug-delivery system to encapsulate the optimal concentration. The effects of these drugs and liposomes were characterized by protein secretion, metabolism, and viability assays. DON and a combination of DON and Que at a low concentration were effective at significantly decreasing pro-inflammatory macrophage secretion for 3 out of 5 human donors. Additionally, DON-loaded liposomes were effective at decreasing THP-1 pro-inflammatory protein secretions at high concentrations. Surprisingly, blank-liposomes were also effective at decreasing THP-1 pro-inflammatory protein secretions. However, the liposome study with primary human macrophages had no decrease in proinflammatory secretions, which may be due to a DON-resistant human donor. Future work is needed to determine why some donors are more sensitive to these molecules than others, and a more rigorous metabolic assay is needed to see if these metabolism-altering drugs are behaving as expected by changing macrophage metabolism.
Metrics
59 File views/ downloads
30 Record Views
Details
- Title
- Altering metabolism repolarizes pro-inflammatory human macrophages
- Creators
- Bhavani Singh
- Contributors
- Kara L. Spiller (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- ix, 65 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991014695141004721