Dissecting the cellular and molecular basis of macrophage-nerve crosstalk in the salivary gland in health and regeneration

Radiotherapy is a life-saving treatment for those with head and neck cancer. Although radiotherapy is very often successful in treating the cancer, a serious side-effect is damage to healthy tissue near the tumour(s), including the salivary glands. This tissue damage results in reduced ability to produce saliva (a condition known as dry mouth or xerostomia), which leads to difficulties with eating, speaking and sleeping. Furthermore, it causes tooth decay and oral health problems. Thus, the side-effects of radiotherapy adversely affect a patient's quality of life.

Existing treatments for xerostomia only give short-term relief and therefore there is a need to develop better, more effective treatments. A treatment that promotes the damaged salivary gland to repair and regenerate would be ideal, however this approach is currently prevented by an incomplete understanding of the repair and regeneration processes that occur in the salivary gland following injury.

We do know that the nerves surrounding the salivary glands are important for producing saliva when it is required. We also know that nerves can send signals to other salivary gland cells to help repair and regeneration of the tissue following injury or inflammation. Radiation treatment also leads to major changes in the immune cells present in the salivary gland. Macrophages are the most abundant immune cell in the salivary gland and they have long been considered key players in the repair and regeneration of many different organs, yet the exact roles they perform in the injured salivary gland remain unclear. In preliminary experiments we have shown that macrophages and nerves closely associate with one another in the salivary gland, but if and how they communicate to promote regeneration has never been studied.

In this project we will investigate whether macrophages and nerves communicate to promote salivary gland repair and regeneration. Specifically, we will determine what happens to the presence and behaviour of nerves if macrophages are removed. Collectively, this will tell us if nerves and macrophages work together during regeneration of the salivary gland, and if we can improve this communication to get better regeneration.

Therapeutic radiation remains a life-saving treatment for those with head and neck cancer (550,000 people annually worldwide). Although radiotherapy is often effective at treating the cancer, it also destroys healthy organs, such as salivary glands, within the field of radiation, leading to difficulties in speaking, eating, and sleeping, and to significant oral health problems, severely affecting patient quality of life. Patients rely solely on short-term solutions which alleviate the symptoms but to date there is no long-term cure. A regenerative strategy would provide a long-term solution but is hindered by an incomplete understanding of the cellular and molecular processes that govern effective tissue repair and regeneration.

In other tissues there is evidence that macrophages play a pivotal role in repair and regeneration, and furthermore, that this may involve macrophage-nerve crosstalk. Whether this crosstalk occurs in the salivary gland following injury is unknown. In this proposal, we seek funding to establish a new collaborative grouping which will bring together expertise in immunology (Bain group) and neuroscience (Emmerson group) to address this important knowledge gap. Specifically, we will set out to determine if and how nerves and macrophages communicate with one another to promote tissue repair and regeneration using state-of-the-art technologies and in vivo experimental models. We will use the data generated in this project to provide a solid case for applying subsequently for larger scale funding.

Given the unrivalled ability of macrophages to orchestrate tissue repair and our previous work identifying nerves as key players of regeneration, understanding the molecular basis of crosstalk between these cells could ultimately provide new therapeutic avenues to promote regeneration in patients with radiation-induced injury of the salivary gland.