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The role of teleost neutrophils in the regulation of inflammation Open Access


Other title
lipid mediators
Type of item
Degree grantor
University of Alberta
Author or creator
Havixbeck, Jeffrey J
Supervisor and department
Barreda, Daniel (Biological Sciences)
Examining committee member and department
Barreda, Daniel (Biological Sciences)
Goss, Gregory (Biological Sciences)
Szymanski, Christine (Biological Sciences)
Belosevic, Miodrag (Biological Sciences)
McKay, Derek (Department of Physiology and Pharmacology, U of Calgary)
Department of Biological Sciences
Physiology, Cell and Developmental Biology
Date accepted
Graduation date
2017-11:Fall 2017
Doctor of Philosophy
Degree level
The inflammatory response is a complex biological process initiated following the recognition of noxious stimuli. It is composed of an elaborate cascade of both pro- and anti-inflammatory mediators, essential for effective defenses against infection, the removal of damaged cells, and the initiation of tissue repair processes. At the core of these responses is phagocytosis, an evolutionarily conserved mechanism critical to immune defense and the maintenance of homeostasis. Phagocytosis is initiated through the recognition of large particles (>1μM) by receptors on the cell surface, leading to actin polymerization, particle internalization, and a diverse array of downstream responses. Neutrophils are essential effector cells that form the first line of defense against invading pathogens. The main objective of my thesis research was to characterize the functional roles of teleost neutrophils, where various mechanisms are involved in the induction of pro-inflammatory responses, the regulation of inflammation, and neutrophil-driven mechanisms of resolution. Similar to mammalian phagocytes, I found that goldfish and lamprey phagocytes contribute to both pro-inflammatory and pro-resolving responses ex vivo. However, I found significant differences with regards to the level of responsiveness to zymosan and apoptotic cells. Interestingly, goldfish phagocytes displayed a reduced sensitivity to apoptotic cells, instead displaying a greater induction of antimicrobial respiratory burst responses during co-stimulation. Moreover, teleost phagocytes remained as central contributors to the resolution phase of inflammation, even though they showcased an improved ability to induce strong antimicrobial inflammatory responses. When I began focusing on neutrophils, I found that the number of circulating neutrophils in teleost fish was far below their mammalian counterparts. Despite this, many other aspects of neutrophil biology and regulation remained the same. Within the hematopoietic tissue, I found that teleost neutrophils exist in a large storage pool, from which they rapidly exit, enter into circulation, and infiltrate the inflammatory site when called upon. It has previously been shown that both mammalian and teleost macrophages exhibit extensive roles in inflammatory control. Interestingly, I demonstrated that neutrophils alter their phenotype throughout the acute inflammatory response, and contribute to both the induction and the resolution of inflammation. Neutrophils isolated during the pro-inflammatory phase displayed elevated ROS responses and released inflammation-associated leukotriene B4. In contrast, neutrophils isolated during pro-resolution displayed low levels of ROS and released lipoxin A4. Notably, eicosanoid release by neutrophils played a role, at least in part, in regulating divergent macrophage responses, including inducing their uptake of apoptotic cells. These observations were then applied to study the teleost inflammatory response following infection with the natural fish pathogens, Aeromonas veronii or Mycobacterium fortuitum. Both bacteria have been associated with significant outbreaks in aquaculture, often leading to mass die offs. I found that similar to the zymosan model, neutrophils rapidly migrated to the site of infection. In addition, both pathogens stimulated the production of ROS in teleost neutrophils. However, neutrophils were only capable of significantly killing A. veronii, unlike M. fortuitum, which required the total population of leukocytes for significant elimination. However, most interestingly, was the capacity of neutrophils to internalize dying macrophages previously incubated with A. veronii, despite remaining unable to internalize other forms of apoptotic cells. Notably, following the uptake of dying macrophages, neutrophils remained viable and increased their production of ROS, remaining pro-inflammatory in nature. Overall, the examination of the teleost inflammatory response mounted against pathogen mimics and natural bacterial infections provides additional insights into the complex mechanisms by which neutrophils operate within an inflammatory site and contribute to the induction and regulation of acute inflammatory responses.
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Havixbeck JJ and Barreda DR (2015) Neutrophil development, migration, and function in teleost fish. Biology 4(4): 715-734Havixbeck JJ, Rieger AM, Wong ME, Wilkie M, Barreda DR (2014) Evolutionary conservation of divergent pro-inflammatory and homeostatic responses in sea lamprey phagocytes. PLoS ONE 9(1):e86255. doi:10.1371/journal.pone.0086255Havixbeck JJ, Rieger AM, Wong ME, Hodgkinson JW, Barreda DR. (2016) Neutrophil contributions to the induction and regulation of the acute inflammatory response in teleost fish. Journal of Leukocyte Biology 99(2):241-52Havixbeck JJ, Rieger AM, Churchill LJ, Barreda DR. (2017) Neutrophils exert protection in early Aeromonas veronii infections through the clearance of both bacteria and dying macrophages. Fish and Shellfish Immunology doi: 10.1016/j.fsi.2017.02.001Havixbeck JJ, Wong ME, More Bayona JA, Barreda DR. (2015) Multi-parametric analysis of phagocyte antimicrobial responses using imaging flow cytometry. Journal of Immunological Methods 423: 85-92

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