The uncharted journeys of inflammatory cells and their functional implications

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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.