Modulation of inflammatory response by cell specific storage endosomes
Even if regulated trafficking of vesicles and their content is essential for a large diversity of cellular processes, the involved factors and mechanisms remain poorly understood. Our results from the last years indicate that the Insulin Responsive Aminopeptidase (IRAP), a type II transmembrane protein, is a dual function factor. As we have previously demonstrated, IRAP is a peptidase involved in antigen trimming required for antigen cross-presentation in dendritic cells. However, we have recently discovered that IRAP plays an essential role in the trafficking of cell-specific storage endosomes, which is independent of its enzymatic function.
Cell-specific storage endosomes are vesicles that show a slow constitutive recycling, but can translocate rapidly to cell surface under cell-specific stimulation. Despite their broad tissues distribution, storage endosomes were until now studied almost exclusively in adipocytes, where they ensure rapid changes in surface protein composition in response to insulin stimulation. Our unpublished results on immune cells show that IRAP storage endosomes regulate the innate immunity by modulation of phagosome maturation, endosomal TLRs signaling and probably cytoskeleton remodeling. In preliminary experiments, systemic deletion of IRAP in mice generated an aberrant inflammatory response, which culminated with animal death during infections.
Based on our preliminary results obtained mainly in dendritic cells, our group aims to investigate the role of IRAP storage endosomes in the inflammatory response in both immune cells and non-immune cells (as endothelium, renal mesangium and epithelium) at two levels:
1) at the cellular level by investigating the cell biology of storage endosomes and their trafficking regulation and
2) at the organism level by creating mouse models with targeted deletion of IRAP in immune and non-immune cells that are active players in inflammation. Since the storage endosomes dynamics is sensitive to external regulation, understanding their function in inflammatory response will provide new potential targets for active modulation of inflammation.
A. The aminopeptidase IRAP is the hallmark of cell-specific storage endosomes. These vesicles have a constitutive slow recycling and can be rapidly translocated to the cell surface under cell specific stimulation (insulin stimulation in adipocytes or IgE-IC in mast cells). In dendritic cells, IRAP and its endosomal compartment are involved in regulation of both, innate and adaptive immunity).
B. IRAP endosomes morphology (immunofluorescent microscopy) in murine dendritic cells.