First Advisor

Pullen, Nicholas A.

Document Type

Dissertation

Date Created

5-2023

Abstract

This research focuses on identifying novel mechanisms through which mast cells (MCs) can be activated, specifically focusing on the effects of transforming growth factor beta-1 (TGF-β1) on MC activation and cytokine release and how these pathways can contribute to disease. We found that MCs can be activated with TGF-β1 alone, inducing degranulation and cytokine release comparable to classical, immunoglobulin-E-mediated activation paradigms. This activated state resembles a described concept in immunology termed trained immunity – a process that allows innate immune cells to potentiate their future immune responses following priming with a stimulus. Hypothesizing that TGF-β1 is a novel stimulus of trained immunity, we observed the metabolic and gene expression changes in MCs stimulated with TGF-β1 in comparison to lipopolysaccharide stimulation to better understand the biological changes associated with a trained immune phenotype. We discovered that priming of MCs induced significant changes in inflammatory and inflammasome-related gene expression during initial priming and restimulation almost a week later, however there were no observable metabolic changes. These findings indicate that MCs respond to secreted cytokines, coupled with gene expression changes, and have the biological machinery associated with inflammasome activation and trained immunity. However, they do not alter their metabolic phenotype to these cues. Taken together, these discoveries illustrate a new role for the MC in various diseases that present with chronic inflammation including cancers. This research includes a review of literature documenting the involvement of MCs in the propagation and persistence of inflammatory diseases. To further study this, MCs were identified in murine mammary adenocarcinomas and found to be significantly increased in tumors lacking the interleukin-6 gene. Given MCs were originally identified within a breast cancer tumor, this discovery suggests that MCs are a critical inflammatory cell whose function can be aberrantly altered in specific tissues, contributing to chronic inflammatory diseases. Mast cells are expressed in almost all tissue types – this study aims to highlight the significance of MCs in inflammation and suggests novel therapeutic options which aim to reduce remove the MC from the inflammatory triad of tissue damage, cytokine release, and immune cell migration/invasion into tissue. Future directions will continue to describe this newly appreciated role for the MC and identify the long-term effects of trained immunity on MC function and activation.

Extent

155 pages

Local Identifiers

Lyons_unco_0161D_11141.pdf

Rights Statement

Copyright is held by the author.

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