Fluvastatin and microRNA-146a alter interleukin-33 mediated mast cell functions.

Mast cells are tissue-resident immune cells known as effector cells for the innate and adaptive immune systems. Mast cells contribute to host defenses against parasites such as large roundworm parasites, bacterial pathogens, and toxins, and participate in wound healing, but they are mostly known for...

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Main Author: Taruselli, Marcela
Format: Others
Published: VCU Scholars Compass 2019
Subjects:
Online Access:https://scholarscompass.vcu.edu/etd/5859
https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=6963&context=etd
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spelling ndltd-vcu.edu-oai-scholarscompass.vcu.edu-etd-69632019-10-20T22:08:50Z Fluvastatin and microRNA-146a alter interleukin-33 mediated mast cell functions. Taruselli, Marcela Mast cells are tissue-resident immune cells known as effector cells for the innate and adaptive immune systems. Mast cells contribute to host defenses against parasites such as large roundworm parasites, bacterial pathogens, and toxins, and participate in wound healing, but they are mostly known for their role in allergic diseases. It has been well established that during allergic diseases, mast cells are stimulated by IgE cross-linkage to release proinflammatory mediators. However, a newly discovered cytokine, IL-33 has also been implicated in allergic disease. Recently, IL-33 has been implicated as a driver of several Type I sensitivities and previous studies have shown that IL-33 can stimulate mast cells in atopic inflammation. Although the importance of IL-33 has been established, there are still several things unknown about IL-33 signaling regulation or treatment. This dissertation will present two separate studies involving the modulation of IL-33-mediated mast cells function In the first study, the effects of fluvastatin are explored. In a previous study, fluvastatin was shown to inhibit proinflammatory functions of IgE crosslinked mast cells. Contrasting to IgE stimulation, fluvastatin augments IL-6 and TNF production in IL-33 stimulated mast cells, but suppressed MCP-1. This phenomenon was seen in mouse and human mast cells in vitro and replicated in a mast cell-dependent murine model of IL-33-induced inflammation in vivo. In the second study, IL-33 was found to induce miR-146a expression in mouse mast cells and mast cell-derived exosomes in vitro, and in plasma exosomes in vivo. IL-33 induced miR-146a was of interest because miR-146a is a known negative regulator of TLR signaling, which shares the MyD88 signaling pathway with IL-33. We found that miR-146a KO mast cells are hyperresponsive to IL-33 stimulation, data that were replicated by suppressing miR-146a-5p in WT mast cells. In an acute mast cell repopulation model, kitW-sh/W-sh mice containing miR-146a KO BMMC had increased IL-33 induced neutrophilia in comparison to their controls. Collectively, these data reveal new IL-33 signaling pathways and means of altering its inflammatory effects on mast cells. Because IL-33 has important roles in allergy and other Th2-mediated diseases, these results advance clinically relevant areas of immunology. 2019-01-01T08:00:00Z text application/pdf https://scholarscompass.vcu.edu/etd/5859 https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=6963&context=etd © The Author Theses and Dissertations VCU Scholars Compass Immunology mast cells IL-33 miR-146a fluvastatin cell signaling Biology Cell Biology Immunity
collection NDLTD
format Others
sources NDLTD
topic Immunology
mast cells
IL-33
miR-146a
fluvastatin
cell signaling
Biology
Cell Biology
Immunity
spellingShingle Immunology
mast cells
IL-33
miR-146a
fluvastatin
cell signaling
Biology
Cell Biology
Immunity
Taruselli, Marcela
Fluvastatin and microRNA-146a alter interleukin-33 mediated mast cell functions.
description Mast cells are tissue-resident immune cells known as effector cells for the innate and adaptive immune systems. Mast cells contribute to host defenses against parasites such as large roundworm parasites, bacterial pathogens, and toxins, and participate in wound healing, but they are mostly known for their role in allergic diseases. It has been well established that during allergic diseases, mast cells are stimulated by IgE cross-linkage to release proinflammatory mediators. However, a newly discovered cytokine, IL-33 has also been implicated in allergic disease. Recently, IL-33 has been implicated as a driver of several Type I sensitivities and previous studies have shown that IL-33 can stimulate mast cells in atopic inflammation. Although the importance of IL-33 has been established, there are still several things unknown about IL-33 signaling regulation or treatment. This dissertation will present two separate studies involving the modulation of IL-33-mediated mast cells function In the first study, the effects of fluvastatin are explored. In a previous study, fluvastatin was shown to inhibit proinflammatory functions of IgE crosslinked mast cells. Contrasting to IgE stimulation, fluvastatin augments IL-6 and TNF production in IL-33 stimulated mast cells, but suppressed MCP-1. This phenomenon was seen in mouse and human mast cells in vitro and replicated in a mast cell-dependent murine model of IL-33-induced inflammation in vivo. In the second study, IL-33 was found to induce miR-146a expression in mouse mast cells and mast cell-derived exosomes in vitro, and in plasma exosomes in vivo. IL-33 induced miR-146a was of interest because miR-146a is a known negative regulator of TLR signaling, which shares the MyD88 signaling pathway with IL-33. We found that miR-146a KO mast cells are hyperresponsive to IL-33 stimulation, data that were replicated by suppressing miR-146a-5p in WT mast cells. In an acute mast cell repopulation model, kitW-sh/W-sh mice containing miR-146a KO BMMC had increased IL-33 induced neutrophilia in comparison to their controls. Collectively, these data reveal new IL-33 signaling pathways and means of altering its inflammatory effects on mast cells. Because IL-33 has important roles in allergy and other Th2-mediated diseases, these results advance clinically relevant areas of immunology.
author Taruselli, Marcela
author_facet Taruselli, Marcela
author_sort Taruselli, Marcela
title Fluvastatin and microRNA-146a alter interleukin-33 mediated mast cell functions.
title_short Fluvastatin and microRNA-146a alter interleukin-33 mediated mast cell functions.
title_full Fluvastatin and microRNA-146a alter interleukin-33 mediated mast cell functions.
title_fullStr Fluvastatin and microRNA-146a alter interleukin-33 mediated mast cell functions.
title_full_unstemmed Fluvastatin and microRNA-146a alter interleukin-33 mediated mast cell functions.
title_sort fluvastatin and microrna-146a alter interleukin-33 mediated mast cell functions.
publisher VCU Scholars Compass
publishDate 2019
url https://scholarscompass.vcu.edu/etd/5859
https://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=6963&context=etd
work_keys_str_mv AT tarusellimarcela fluvastatinandmicrorna146aalterinterleukin33mediatedmastcellfunctions
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