Signal Integration during Phagocytosis

Morrissey Project Summary: (30 lines) The long-term goal of this project is to understand how cells control their sensitivity to external stimuli. Macrophages are a particularly interesting example of this because they constantly encounter background stimuli, like IgG, in their surrounding environment. Macrophage signaling pathways are carefully tuned to rapidly detect IgG-bound pathogens without reacting to healthy cells. Macrophages respond to IgG by activating phagocytosis and/or inflammation. The short-term goal of this project is to define how macrophages set a response threshold for these outputs. We are approaching this problem from two directions. The first direction is examining how receptor clustering or co-clustering affects macrophage sensitivity. Our previous data shows that clustering of activating ligands enhances activation of the Fc Receptor, and increases phagocytosis. Phagocytosis is also controlled by inhibitory ‘Don’t eat me’ signals on viable cells. We are now expanding our studies to examine how clustering of inhibitory ligands, and co-clustering of inhibitory and activating ligands affects phagocytosis. This will suggest how ligand or receptor pattern can tune macrophage sensitivity. Our second direction is examining the intracellular signaling that filters out sub-threshold stimuli. Our preliminary data suggests that a higher IgG signal is required for inflammation than phagocytosis. We will address the following questions: What parameter do macrophages measure to determine IgG signal intensity – signal duration, IgG density, or total number of IgG molecules? What is the molecular breakpoint in the IgG signaling pathway that is only activated by high IgG? How does IgG stimulus intensity affect signaling dynamics in the NFkB and MAPK signaling pathways? Overall, this will suggest how macrophages are able generate two separate responses from a single input based on dose.