Decoding neutrophil decision making – the chase and the kill

Neutrophils are the most abundant immune cell in the human body and are critically important in clearing infections and in wound healing. They rapidly migrate from circulation to sites of injury or infection by detecting chemicals that are released by the body or that emanate from degrading cells and bacteria. Upon reaching these sites, neutrophils engage pathogens with direct killing processes including pathogen engulfment by phagocytosis and by releasing pre-stored anti-microbial products from specialized vesicles called granules in a process called degranulation. While these destructive processes are effective at neutralizing pathogens, dysregulated activity is implicated in inflammatory diseases. Cleary defining the molecular mechanisms that regulate immune cell functions would present opportunities for new drug targets and therapeutics. However, achieving the comprehensive understanding necessary to derive novel therapies has been hampered by the complex interactions between molecules that regulate neutrophil functions. This dissertation is compilation of my contributions toward untangling these molecular pathways. Chapter 1 provides an introduction to neutrophils, their functions, and an overview of outstanding related questions. Chapter 2 describes discoveries about how neutrophils prioritize competing signals as they migrate, which helps them home in on the correct target. The work described in chapter 2 was a collaboration project with Briana Rocha-Gregg. Chapter 3 focuses on neutrophil function once they reach sites of infection. Specifically, it describes my findings about the molecular pathways that control degranulation, including the identification of components that may distinguish migration and degranulation behaviors. In Chapter 4 closing remarks and comments on future directions are made.