Interrogating monocyte-stromal cell crosstalk in the intestine

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Macrophages are one of the most abundant leucocytes in the intestinal mucosa where they play fundamental roles in maintaining tissue homeostasis and repair following injury, insult or inflammation. However, they are also implicated in the pathology of inflammatory bowel disease (IBD), where they appear to drive disease. Importantly, we have shown that both pro-inflammatory macrophages and homeostatic/pro-resolution macrophages derive from the same classical monocyte precursor. While our work has established that the differentiation of monocytes occurs immediately as they enter the gut mucosa and is influenced by the presence of the microbiota, the exact factors that control monocyte differentiation remain elusive. Extravasation and migration in the mucosa will undoubtedly involve crosstalk with different structural, non-haematopoietic cells, including endothelia, pericytes, fibroblasts and epithelial cells, yet the nature of this crosstalk and how it influences monocyte differentiation is completely unexplored. Moreover, how the microbiota and its derivatives influence this crosstalk remains poorly understood.In this project, the student will use a co-culture system to interrogate the crosstalk between monocytes and intestinal stromal cells, using both mouse and human cells, and how this might change across the life course and following inflammatory challenge. Moreover, we will determine how this might change in the context of dysbiosis. Techniques will include multi-parameter flow cytometry, confocal microscopy, cytokine/chemokine arrays and transcriptional profiling. The student will be fully trained in all these techniques as well as in statistics, presentation skills, writing skills, and data management.