Abstract P3170: Immunomodulatory Effects Of Exosomes From Epigenetic Drugs-Stimulated Macrophages

Abstract

Background: Exosomes have significant therapeutic promise; however, a key problem prohibiting and exploring exosomes in clinical therapy is the availability of disease-specific exosomes. Our recent in vitro and in vivo studies identified that combined treatment with Procainamide (P, DNMT1 inhibitor) and Tubastatin A (T, HDAC6 inhibitor) reduces inflammation upon lipopolysaccharide (LPS) stimuli. Here, we elucidate the therapeutic potential of exosomes derived from the macrophages treated with P+T during the inflammatory condition. Hypothesis: We hypothesize that exosomes derived from LPS-challenged macrophages (THP1) treated with P+T will provide a better anti-inflammatory response than direct drug treatment. Methods and Results: Macrophages were grown in exosome-depleted media for 72 hrs and stimulated once with LPS, P+T, or L+P+T for exosome collection. These exosomes were used for treating LPS-challenged macrophages. qRT-PCR analysis was performed to check for the expression of pro-inflammatory genes after exosome treatment. Our results show that LPS-challenged macrophages treated with exosome from L+P+T showed significantly reduced expression of TNFα and IL1β when compared to the direct drug treatments (Fig. A, B) . We also observed that the pro-inflammatory microRNAs such as miR-21 and miR181-a were significantly reduced in the L+P+T stimulated exosome group (Fig. C, D) . Conclusions: We show for the first time that drug-stimulated exosomes are more effective in reducing inflammation than direct drug treatment. These specific exosomes could be used for infection-related therapy.