Neutrophils and macrophages—the immune system’s first responders—do not simply stay put after fighting an infection; they travel to other parts of the body, and no one knows why. This project aims to track those journeys in living zebrafish, using real-time imaging and genetic tools, to discover where these inflammatory cells go after leaving a wound or infection site, what molecular signals guide them, and what they do when they arrive. The knowledge gap is significant: current research focuses on how immune cells *arrive* at inflamed tissue, but almost nothing is known about their long-term fates after the initial response. Understanding this could reshape how we treat chronic inflammatory diseases—from arthritis to neurodegeneration—by revealing new ways to either stop harmful inflammation or boost the body’s own resolution and defence mechanisms. This is fundamental science. There is no immediate practical application. But similar work on immune cell migration in zebrafish has previously uncovered unexpected mechanisms of tissue repair and cancer surveillance, suggesting that mapping these hidden journeys could eventually lead to new biomarkers for detecting inflammatory states or therapies that guide immune cells toward healing rather than harm.
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Inflammation is a physiological response to injury or harmful agents that ensures tissue defence from invading microbes. This is achieved through inflammatory cells, such as neutrophils and macrophages (also called 'myeloid cells'), which rapidly migrate to damaged loci and execute crucial antimicrobial and tissue repair functions. However, excess or maladaptive inflammation is linked to a range of diseases, from autoimmunity to cancer and neurodegeneration. A key problem in targeting inflammation is our limited understanding of the migration patterns of myeloid cells in vivo. Studies have focused on how these cells reach inflammatory loci, while little is known about their long-term fates. This is important to understand, as increasing evidence reveals that myeloid cells disseminate to other tissues from inflamed lesions, which has implications in resolution of inflammation and host defence. Here, we propose to combine in vivo imaging, genetic manipulations and single-cell transcriptomics in a tractable vertebrate (zebrafish), to elucidate the mechanisms of myeloid cell dissemination, define the identity of disseminating cells and their functional implications. First, we will determine the migration routes of neutrophils and macrophages after microbial encounter, through live imaging and cell tracing, and define the underlying molecular mechanisms, through genetic perturbations. Secondly, we will determine the properties of disseminating inflammatory cells, through single cell transcriptomics, which will generate functional and mechanistic hypotheses for this study and reveal new biomarkers for detection of in vivo inflammatory states. Finally, we will elucidate functions of these cells in immunosurveillance, by tracing the behaviour of individual cells from one infection to the next. This work will fill a major knowledge gap on how inflammatory responses unfold in vivo and shape new ideas for manipulating inflammation towards improved resolution or host defence.
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