Deciphering macrophage versus neutrophil signaling and effector functions in immune responses in vivo

项目总结/文摘

Project Summary/Abstract Immune responses are the result of a combined effort of multiple cell types. In innate immune responses the activity of both macrophages and neutrophils is important in targeting pathogens, resolving tissue damage, and maintaining homeostasis. My laboratory uses the larval zebrafish model to determine the differential role and functions of these two innate cell types in inflammatory responses. The overarching goal of my research program is to identify specific signaling pathways, including signals, receptors, and effector mechanisms, that are required for the function of macrophages versus neutrophils. During human disease, the function of just a subset of these cells may go awry, yet common treatments target broad pathways that inhibit multiple cell types and therefore cause harmful side effects. Identification of discrete mechanisms used by single cell types in inflammatory disease will provide targets for future precision therapies. We have developed an experimental system in larval zebrafish using the fungal pathogen A. fumigatus that separates the function of macrophages and neutrophils. Over the next five years, we propose to combine this system with genetic targeting tools and chemical inhibitors to interrogate the requirement of intracellular killing mechanisms, cell death pathways, Toll-like receptors, and C-type lectin receptors in macrophage versus neutrophil functions against A. fumigatus and in response to PAMPs and DAMPs. In future research, we will expand our experimental model to interrogate the role of these genes and pathways in other inflammatory scenarios, such as sterile inflammation during auto-inflammatory disease. Altogether, this research will delineate complete pathways differentially required for innate immune cell function.