The immune and nervous systems are the body’s main sensory systems that process and respond to environmental stimuli. Both systems can recall earlier challenges and events, leading to responses that are tailored to everchanging conditions. Immune responses are at the basis of keeping organisms healthy and protect them from outside aggressors. For instance, vaccines activate the immune system to mount a protective response against infectious diseases. Similarly, the brain allows us to learn from dangerous situations, so that they can be avoided later to avoid harm. Recent studies revealed that neuronal cells dialogue with immune cells in many of our organs that are exposed to the outside world, such as the lungs. These findings provoke a change in our understanding of how our body works to preserve health, but also lays the foundation for the discovery of new therapeutic strategies by taking advantages of this system. However, we currently lack the knowledge of how these “neuroimmune” networks look like, and how these two complex systems communicate.
In this project, entitled “Tracing of pulmonary neuro-immune networks” (TOPNIN), we focused on group 2 innate lymphoid cells (ILC2). These immune cells are strategically positioned at mucosal surfaces, regulating mucosal defense, tissue homeostasis and inflammation. In the lung, ILC2 contribute to the pathogenesis of allergic airway diseases, such as asthma. The host laboratory and other researchers have previously shown that ILC2 exert their function in the context of neuro-immune cell units that respond to environmental signals, steering mucosal immunity and repair. Nevertheless, the identity of the neuronal circuits innervating neuro-immune cell units and the nature of the bidirectional neuron-immune signals steering mucosal physiology remain elusive.
Therefore, in this Marie Skłodowska-Curie action, we developed new tools that allow us to discover the architecture of the system. We made use of the latest knowledge and tools from neuroscience and immunology, and combined this to develop a technology platform that we call KISS: Kindle of Intercellular Signals and Synapses. We used a combination of viruses that are labeled with fluorescent proteins to specifically label the neurons that communicate with immune cell subsets. By using light sheet microscopy, we were able to generate a three-dimensional atlas of the neurons that innervate these immune cells.
In addition, we combined advanced genetic and molecular approaches to determine how the neurons that innervate neuro-immune cell units in the lung, influence immune cell functions. We found that modulation of the neurons that connect to pulmonary immune cells leads to an altered function of the latter. This is a first step toward understanding how neuro-immune pathways steer homeostasis at the level of organs and the whole organism.
We are currently further exploring the interactions between other immune cells and neuronal networks, not only in the lung, but also in other organs. We seek to unravel the ‘language’ of neuro-immune communication and to discover the different dialects in various organs. In this way, we will gain a better understanding of this new paradigm in mammalian physiology, paving the way for the development of new strategies to promote health, and to prevent disease.
