Neuro-endocrine regulation of immunity – SensorImmune

Survival of organisms depends on their capacity to mount a defense against environmental agents that cause tissue damage and infection. The nervous system and the immune system are both involved in the detection of these “dangers” but they are traditionally thought of as serving separate functions. However, anatomical and cellular bases for bidirectional interactions between these two systems have been established and a new paradigm on a regulatory role of the nervous system on immune functions is emerging. Indeed, upon a local or a systemic inflammation/infection, the nervous systems produces a number of mediators that can impact the immune system and reciprocally.
First, when a local infection/inflammation occurs in tissues, sensory nerves are stimulated, convey the damaging information to the brain and release a number of mediators that could mediate the local modulation of immunity. Second, upon infections or inflammatory processes, nerve fibres from the sympathetic nervous system (SNS) release the neurotransmitter noradrenaline into lymphoid organs and into tissues. SNS nerve fibres can also stimulate the adrenal glands to release stored adrenaline into the blood circulation. Both of these neuromediators can stimulate adrenergic receptors on leukocytes. The goal of our project is to extend the spectrum of our knowledge on regulatory mechanisms affecting the immune response by investigating the functional role of the nervous system on immunity.
Because of the complexity of these two systems and the multiplicity of the factors which could be involved, we decided to tackle this highly challenging question by using two parallel approaches based on very well characterized biological and genetic tools. First, we will explore the function of sensory neurons and pain sensitivity on immunity in models of skin immunization (specific aim 1). Second, we will analyse the role of adrenaline and noradrenaline on immune responses generated during a systemic viral infection (specific aim 2).
In the first part of the study (specific aim 1), we will use 3 unique genetic mouse models in which primary sensory neurons innervation of the skin is either defective or completely abolished. These mice exhibit an impaired sensitivity to injury and inflammation-induced pain and will be used as valuable tools to test the in vivo role of sensory nerves on the immune response. Our preliminary results are very promising as we already demonstrated that lack of sensory skin innervation affect both the local and systemic innate and adaptive immune responses following intradermal vaccination. In this part of the project, we will apply a series of molecular and cellular approaches to decipher the mechanisms involved in this process.
In the second part of the study (specific aim 2), we will analyse the role of adrenaline and noradrenaline on innate immune cells. In particular, we found that the function of natural killer (NK) cells can be modulated by these neuroeffector molecules via the ß2-adrenergic receptors (ß2-AR). We will study ß2-AR-deficient mice and use a conditional gene targeting approach to selectively inactivate ß2-AR gene in these innate lymphocytes. NK cell functions will then be analysed at steady state and upon infection with mouse cytomegalovirus (MCMV).
Our project is both ambitious and exploratory. We propose to characterize the interactive network between cutaneous nerves, the SNS, and the immune system. It is based on a close collaboration between two groups specialized respectively in Immunology and Neuroscience and on promising preliminary data. It will benefit from available genetic mouse models with which we already generated. This study should reveal new components of the integrated host response to pathogens with important implications for our knowledge of both the nervous and the immune systems and for the design of new vaccines and innovative therapies. It also aims at opening new avenues of research on neuro-immune interactions.