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Dissertation
Role of macrophage derived small extracellular vesicles (sEVs) in regulation of T cell mediated resolution of inflammatory pain
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2023
DOI:
https://doi.org/10.17918/00001643
Abstract
Chronic pain is the most prevalent, disabling, and expensive public health condition in the United States. Aberrant neuroimmune signaling underlies the development of chronic pain. Small extracellular vesicles (sEVs) play an important role in intercellular communication and are critically involved in mediating immune modulatory effects. Currently, very little is known about signaling mechanisms by which sEVs modulate inflammatory pain. We observed that sEVs from RAW 264.7 macrophage cells show therapeutic efficacy in a complete Freud adjuvant (CFA) mouse model of inflammatory pain in both male and female C57BL/6j mice. sEVs from antigen presenting cells (APCs) such as macrophages express major histocompatibility complex (MHC) and costimulatory molecules and thereby activate T cells. As T cells have been shown to be important for pain resolution, we hypothesized that macrophage-derived sEVs promote resolution of inflammatory pain hypersensitivity by modulating host T cell responses. While sEVs were unable to directly activate isolated T cells in vitro, sEV treatment of total splenocytes induced the activation of APCs and T cells. Intrathecal administration of sEVs in the CFA model showed lower frequencies of pro-inflammatory T helper 1 cells and increased immunosuppressive regulatory T cells. sEV treatment also enhanced TGF-[beta]1 production. Smad7 binds to TGF-[beta]1 receptor and inhibits TGF-[beta]1 driven Smad signaling. Our in vitro studies showed that miR-21 transfer by sEVs inhibited Smad7 mRNA in recipient T cells. We also observed that sEVs released by RAW 264.7 derived sEVs harbor both activated and latent TGF-[beta]1 on their surface. To evaluate if T cells were required for the sEV mediated resolution of inflammatory pain, we performed adoptive transfer of T cells into RAG2-/- mice. We observed that administration of sEVs increased the pro-resolution effects of T cells and that T cells were both necessary and sufficient for sEV mediated resolution of inflammatory pain. sEVs may represent a novel strategy to promote the endogenous pain resolving role of T cells in vivo without the cost and technical challenges associated with personalizing T cell therapies. Our studies suggest a novel strategy to promote the endogenous pain-resolving role of T cells by sEVs.
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Details
- Title
- Role of macrophage derived small extracellular vesicles (sEVs) in regulation of T cell mediated resolution of inflammatory pain
- Creators
- Richa Pande
- Contributors
- Seena Ajit (Advisor) - Drexel University, Pharmacology and Physiology
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvi, 243 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 991020503315004721