Investigating the Role of Paracrine Signaling in the Regulation of the Inflammatory Response in Macrophages

Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Mathematics

First Advisor

Miller-Jensen, Kathryn

Abstract

Macrophages serve as key effector cells of the innate immune system, playing a crucial role in combating infections and maintaining homeostasis. Inflammatory macrophages mediate their effects through the secretion of cytokines and chemokines, orchestrating cellular responses across both the innate and adaptive immune systems to counteract pathogenic threats. Among the most extensively studied signaling pathways in innate immunity is the Toll-like receptor 4 (TLR4) pathway, which is activated upon recognition of its canonical ligand, lipopolysaccharide (LPS). Activation of TLR4 triggers a highly heterogeneous transcriptional and secretory response in macrophages, reflecting their functional specialization in distinct physiological and pathological contexts. The mechanisms underlying the heterogeneity of the macrophage secretion response, as well as its impact on the overall immune response, have been previously investigated. However, the broader spatial properties of the microenvironment, which are critical in physiologically relevant contexts, remain elusive. Additionally, existing frameworks in macrophage biology often overlook key variables, such as cell density, which play a fundamental role in coordinating collective immune responses. To investigate positive and negative feedback mechanisms in macrophage activation, we analyzed the signaling dynamics of the proinflammatory cytokine tumor necrosis factor (TNF) and the anti-inflammatory cytokine interleukin-10 (IL-10). The regulatory feedback and the intercellular signaling mechanisms involved in this system serve as a model for quorum sensing in collective activation and spatial patterning. In order to study the effects of density on this system, we have characterized the intercellular regulatory feedback system through extensive in vitro studies and have modeled and analyzed patterns of collective activation as a function of density.

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