Neuroimmune regulation of peripheral immune responses by modulation of food intake and energy balance

Recent advances in cross-disciplinary research have revolutionised our understanding of how the immune system is regulated by a broad range of external and internal signals that ensure optimal immunity and human health. In particular, changes in diet or availability of nutrients can have profound effects on the activity of the immune system to keep us healthy and to prevent infections, yet the mechanisms through which this is achieved remain poorly defined.
The nutritional status within the body is sensed by nerve cells positioned in specific areas of the brain. By working together, these nerve cells create feelings of hunger or fullness, and in turn regulate food consumption and dietary choices by sending signals to organs throughout the body. Importantly, it is now also appreciated that many organs that play an important role for optimal immune responses are highly innervated and that many immune cells can respond directly to neurochemicals released by nerve endings.
Here, we aim to investigate the hypothesis that the brain nerve cells that sense normally sense nutrient levels and control feeding activity, also possess secondary functions as direct regulators of the immune system in health and disease.
In exciting preliminary findings, we found that activity of these nerve cells specifically is sufficient to drive changes in immune cell activity in a number of organs in the body. Surprisingly, many of these effects occur regardless of food consumption. Moreover, we also found that inflammation itself, on the other hand, impact on the normal way these nerve cells process food and food-related signals.
In this project, we will consolidate and build on these exciting and completely new discoveries. We will make use of a wide range of cutting-edge technologies that allow us to selectivity turn discrete nerve cells in the brain on or off, as well as to visualise them in action as they are sensing nutrients. This work will be possible thanks to an existing multidisciplinary collaborative team with expertise in Neuroscience, Metabolism and Immunology. We expect that our finding will provide a solid evidence base for a previously unappreciated crosstalk between the brain mechanisms that control our feeling of hunger and fullness and the peripheral immune system, with important implications for the treatment of infectious and inflammatory disease, as well as metabolic health.

Technical Summary
Caloric restriction improves inflammatory diseases, however the underling mechanisms are poorly understood. Recent evidence suggests that nutritional states have potent effects on the peripheral immune system, both in model organisms and humans. Moreover, it is also well established that the brain function as a master regulator of energy balance and that change in nutritional states are associated with activity changes of distinct neuronal circuits dedicated to energy sensing and appetite control. However, despite this intimate interconnection, it is not known whether nutrient availability modulates immune processes via direct effects on immune cell metabolism or independently via neuronal regulatory pathways.
Our overarching hypothesis is that appetite-controlling brain systems have parallel immunoregulatory functions and that their activity participates in the immunomodulation that occurs upon changes in caloric intake.
To test our hypothesis, we propose a synergistic collaborative approach, using the latest genetic technologies to manipulate brain activity in combination with cutting-edge and comprehensive immunological techniques. By experimentally manipulating critical appetite-controlling neurones we will be able to disconnect their activity from systemic nutrient levels and interrogate their net contribution to peripheral immune homeostasis and inflammatory outcomes. We will also use a novel technology to measure neuronal activity in vivo and study how immune system activation impact on the activity of critical appetite-controlling neurones.
The proposed work is timely, novel and will provide an evidence base, and capacity-building scope, for a previously unappreciated cross-talk between neuronal circuits that control appetite and peripheral immune responses. This has the potential to disclose new mechanisms of neuroimmune interactions and aid in the development of novel therapeutic strategies in a range of inflammatory and metabolic disease.