Altering Metabolism Repolarizes Pro-Inflammatory Human Macrophages
Friday, May 8, 2020
10:00 AM-12:00 PM
BIOMED Master's Thesis Defense
Title:
Altering Metabolism Repolarizes Pro-Inflammatory Human Macrophages
Speaker:
Bhavani Singh, Master's Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University
Advisor:
Kara Spiller, PhD
Associate Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University
Details:
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 repolarize macrophages from an M1 phenotype. 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.
The results showed that 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.
Contact Information
Ken Barbee
215-895-1335
barbee@drexel.edu