Sponsor
Portland State University. Department of Biology
First Advisor
Brooke Napier
Term of Graduation
2024
Date of Publication
6-4-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (Ph.D.) in Biology
Department
Biology
Language
English
Subjects
C3aR, Complement, Cytokine, Inflammation, Macrophage
DOI
10.15760/etd.3784
Physical Description
1 online resource (vii, 102 pages)
Abstract
The complement system is an integral part of the innate immune response, and consists of a series of proteins that are mostly (although not exclusively) synthesized in the liver that circulate in the plasma as inactive precursors, as well as receptors on the surface of immune cells. In immune cells such as macrophages, recognition of pathogens by Toll-like receptors (TLRs) leads to the initiation of inflammation and triggers complement activation through a coordinated sequential enzyme cascade that results in the production of bioactive C3a, which interacts with membrane-bound receptor C3aR to regulate innate immune cell function and outcome of bacterial infection. There have been many reports showing C3aR enhances inflammatory responses following lipopolysaccharide (LPS) challenge in vitro and in vivo; however, C3aR-dependent regulation of inflammation remains largely uncharacterized in macrophages. We previously identified a novel role for C3aR as a critical modulator of IL-6 and TNF production in macrophages. Thus, this dissertation aims to recapitulate and build upon the aforementioned role of C3aR by utilizing two well-defined in vitro models challenged with LPS: bone marrow-derived macrophages from global C3aR knockout mice (C3aR1-/-) and wild-type (WT) mice treated with the small-molecule C3aR inhibitor SB290157 (C3aRi) during lipopolysaccharide (LPS) challenge. In Chapter 1, I provide the pertinent background information regarding the topics discussed within this dissertation and offer a preview of the research presented herein. In Chapter 2, I review historical studies on complement-mediated immunity and reveal the conflicting results obtained with C3aR1-/- mice, and also highlight the need for cell-specific C3aR knockouts to better understand how C3aR modulates inflammatory responses. In Chapter 3, we identify discordance in regulation of inflammation by C3aR between C3aRi-treated WT and C3aR1-/- BMDMs, leading to a bifurcation in regulation of inflammatory cytokines IL-6, TNF, and IFNβ. Additionally, I show that C3aR is required for mitochondrial respiration and glycolysis during homeostasis and LPS challenge in primary murine macrophages. Lastly, in Chapter 4, I provide a summary of our findings in context of the literature reviewed in Chapter 2, and suggest future avenues of research in characterizing the functional role of C3aR.
Rights
© 2024 Jesse Alan Corcoran
In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/ This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
Persistent Identifier
https://archives.pdx.edu/ds/psu/42274
Recommended Citation
Corcoran, Jesse Alan, "Characterizing the Role of the Complement Receptor C3aR in Regulating Inflammatory Responses and Mitochondrial Function in Activated Macrophages" (2024). Dissertations and Theses. Paper 6652.
https://doi.org/10.15760/etd.3784