ILCSIGNALLING · Deciphering cell-cell and cell-microbiome interactions of innate lymphoid cells at the single cell level

Deciphering cell-cell and cell-microbiome interactions of innate lymphoid cells at the single cell level

The gastrointestinal tract encompasses a large and diverse microbial ecosystem, termed the gut microbiome which extensively interacts with gut immune system, ensuring tolerance in times of ‘peace’ yet potently reacting against invading pathogens. Recently discovered innate lymphoid cells (ILCs) appear to be a key player in the immune network of the gut, as they function in regulation of homeostasis between gut resident commensal microbiota and immune system, which involves connecting innate and adaptive immunity. Yet, the heterogeneity of this cell compartment is not fully understood as well as the extent of cell-to-cell interactions involved in these process. Similarly, in the other key organ of gastrointestinal system, the liver, the extent of interaction of cells and the impact of the microbiota is not clear, both in health and in disease, such as acute liver failure. Treatment of ALF is limited, mainly consisting of supportive care and liver transplantation. The key objective of this project is to develop a quantitative single-cell transcriptomics-based analysis method to gain comprehensive describe cells of the gastrointestinal system in health and disease, understanding of cell-to-cell communication network in the immune system in health and disease and decipher the impact of the microbiota. This is important, as dysregulation of the immune system of the gut leads to inflammatory diseases such as IBD, more severe outcomes of gastrointestinal infections and more severe outcomes of liver diseases. The objective of this study is to understand cellular and molecular mechanisms driving interactions between cells under stress in the disease model. We identified population of ILCs that are microbiota dependent, in absence of microbiota the number of ILC1 dramatically decreases, and these cells are replaced by ILC3p subpopulation. This leads to skewing the signalling balance in the liver, as ILC1 are producers of key soluble factors such as interferon gamma nad Ccl5. We also deeply characterised the process and found molecular mechanisms driving infiltration of monocytes to the liver upon liver damage. We observed amelioration of the acute liver failure in mouse model targeting TLR signalling, MAPK pathway, Myc transcription factor and microbiota, suggesting that these targets we have identified may indeed be clinically relevant. Hence, we demonstrated that a detailed ALF cellular decoding may enable pathway-specific therapeutic intervention.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз