Potential chemical inhibitors of inflammasomes modulate microglial and astrocytic functions
department or school: Science, Irving K. Barber Faculty of (Okanagan)
department or school: Biology, Department of (Okanagan)
data provider: DSpace
degree campus: UBCO
creator: Greuel, Bridget Kaytie
issued: 2023-04-14T21:05:42Z
issued: 2023
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Alzheimer’s disease (AD) is the sixth leading cause of death worldwide and is characterized by chronic neuroinflammation. Microglia are the brain immunocytes, which normally support and protect neurons; however, they can become adversely activated contributing to onset and progression of neuroinflammation. In addition, defective phagocytic activity of microglia has been suggested to contribute to AD pathogenesis. Astrocytes maintain brain homeostasis but can also become adversely activated leading to the production of excessive pro-inflammatory cytokines and alteration of astrocytic phagocytic activity. Nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor (NLRP) 3 inflammasomes are intracellular protein complexes responsible for the activation and production of pro-inflammatory cytokines by immune cells, including microglia and astrocytes. The inflammasome inhibitors, MCC950, shikonin, and oridonin, have previously been shown to suppress inflammasome activation through several different mechanisms and reduce inflammatory activity of peripheral immune cells; however, the full spectrum of the effects of these drugs on the brain cells is still unknown. I hypothesized that MCC950, shikonin, and oridonin regulate a broad range of immune responses by microglia and astrocytes. Therefore, I studied the effects of these inflammasome inhibitors on murine and human microglia-like cells and human astrocytic cell lines that were challenged with established immune stimulants to induce pro-inflammatory responses. MCC950, shikonin, and oridonin decreased the secretion of nitric oxide and glutamate by murine microglia-like cells; however, none of the inflammasome inhibitors had a significant effect on their secretion of interleukin (IL)-1β or tumor necrosis factor-α (TNF). In human microglia-like cells, MCC950 significantly reduced the secretion of IL-1β, but not TNF, while shikonin and oridonin did not influence the secretion of either of these cytokin…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/84202
note: Potential Chemical Inhibitors of Inflammasomes Modulate Microglial and Astrocytic Functions By Bridget Kaytie Greuel B.Sc., Colorado State University, 2019 A THESIS SUBMITTED In PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE COLLEGE OF GRADUATE STUDIES (Biochemistry and Molecular Biology) THE UNIVERSITY OF BRITISH COLUMBIA (Okanagan) April 2023 © Bridget Kaytie Greuel, 2023 ii Committee Recommendation Form The following individuals certify that they have read, and recommend to the College of Graduate Studies for acceptance, a thesis entitled: POTENTIAL CHEMICAL INHIBITORS OF INFLAMMASOMES MODULATE MICROGLIAL AND ASTROCYTIC FUNCTIONS submitted by Bridget K. Greuel in partial fulfillment of the requirements of the degree of Master of Science (M.Sc.) . Dr. Andis Klegeris, Department of Biology Supervisor Dr. Julien Gibon, Department of Biology Supervisory Committee Member Dr. Wesley Zandberg, Department of Chemistry Supervisory Committee Member Dr. Stephen McNeil, Department of Chemistry University Examiner iii Abstract Alzheimer’s disease (AD) is the sixth leading cause of death worldwide and is characterized by chronic neuroinflammation. Microglia are the brain immunocytes, which normally support and protect neurons; however, they can become adversely activated contributing to onset and progression of neuroinflammation. In addition, defective phagocytic activity of microglia has been suggested to contribute to AD pathogenesis. Astrocytes maintain brain homeostasis but can also become adversely activated leading to the production of excessive pro-inflammatory cytokines and alteration of astrocytic phagocytic activity. Nucleotide-binding domain leucine-rich repeat and pyrin domain-containing receptor (NLRP) 3 inflammasomes are intracellular protein complexes responsible for the activation and production of pro-inflammatory cytokines by immune cells, including microglia and astrocytes. The inflammasome inhibitors, MCC950, shikonin, an…
has type: Thesis/Dissertation
date issued: 2023-05
is shown at: 10.14288/1.0431044
language: eng
degree discipline: Biochemistry and Molecular Biology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Klegeris, Andis
type: Text
identifier URI: http://hdl.handle.net/2429/84202