Investigating nerve:immune cell cross talk during gut inflammation

The gut contains more nerves than any other part of the body outside the brain. These nerves contribute to pain responses and essential muscle movement, but their role during inflammation is not known. The loss of gut nerves, for instance in inflammatory bowel diseases has a huge impact on gut function but may also drive the disease. Our central hypothesis is that nerve:immune cell interaction plays a crucial role in homeostasis and resolution of inflammation in the gut. It is widely accepted that mucosal surfaces represent an actively regulated environment, although the precise mechanisms are poorly understood. This proposal builds on our recently published data, which shows that splenic dendritic cells respond to neuropeptide calcitonin gene-related marker (CGRP) with upregulation of IL-10 secretion and downregulation of activation marker CD80/86, suggesting an immunoregulatory phenotype. We have shown that CGRP+ nerves are abundant in colon, therefore we hypothesise that nerve-derived CGRP contributes to the regulatory dendritic cell/macrophage phenotype observed in the gut. Furthermore, published studies of skin and lung have indicated that a proportion of resident dendritic cells express the receptor for CGRP (RAMP1), and that their response to CGRP may prevent migration to the draining lymph node. If these functional effects hold true in the colon, this will have huge impact on our understanding of what maintains a regulated mucosal interface, and ultimately what constitutes a ‘healthy’ gut.

Training/techniques to be provided:
The project will use flow cytometry, immunohistochemistry, genomic and bioinformatics approaches to investigate the role of CGRP and dendritic cell function during colitis. The Pennock lab has expertise in gut inflammation and mouse models of colitis using genomic and transcriptomic approaches to understand molecular pathways. The MacDonald group has significant expertise in mucosal immune responses, dendritic cell biology and multi-parameter flow cytometry. The project will also take advantage of key core facilities in flow cytometry, imaging, bioinformatics and genomics, all of which have contributed to previous publications from the supervisory team.

Both supervisors are members of the Manchester Immunology Group (MIG, comprising 20 principle investigators) which has an extensive publication record and expertise in the study of cellular and translational immunology, using in vitro and in vivo approaches. This provides a stimulating and cutting edge environment for staff and students alike, maintaining high quality discussion through regular presentations, peer review and output.