Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - NEURIMMUNE (Neural regulation of immunity)

Teaser

The survival of living organisms depends on their capacity to mount a defense against environmental agents that cause tissue damage and infection. Traditionally, the activity of the immune system in repairing tissue injury and combating pathogens has been considered quite...

Summary

The survival of living organisms depends on their capacity to mount a defense against environmental agents that cause tissue damage and infection. Traditionally, the activity of the immune system in repairing tissue injury and combating pathogens has been considered quite different from that of the nervous system, which transduces environmental or internal damaging signals into electrical activity to produce reflexes and sensations. However, anatomical and cellular bases for bidirectional interactions between these two systems have been established. Our laboratory investigates how neural and immune signals are interconnected and integrated to shape the host response to pathogens and injuries.

Stress can be defined as a state of altered homeostasis resulting from external or internal stimuli, including inflammatory processes, infections and pain. In response to these stimuli, various adaptive neuroendocrine mechanisms are induced to restore homeostasis. Part of this response is initiated within the central nervous system and translated into action by the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system. These neuroendocrine pathways have been shown to modulate inflammatory and immune responses. In addition, sensory nerves are stimulated when an injury, an infection or an inflammation occurs in tissues. These neurons convey the damaging information to the brain (inducing pain) and release a number of mediators and neuropeptides in situ that can modulate the function of immune cells locally. A new paradigm in which the nervous system regulates immune functions is emerging. The goal of the project is to identify new regulatory mechanisms affecting the immune response by investigating the functional role of the nervous system in immunity.

Work performed

We are analyzing the role of neuroendocrine pathways in regulating immune responses. Our studies are divided in two main parts:
1) Role of sensory neurons in regulating skin immune response upon injury or infection.
Nociceptors are primary sensory neurons that detect noxious stimuli and inform the brain of the occurrence of inflammatory processes. All tissues highly exposed to the external environment, such as the epithelial surfaces of the skin, are densely innervated by nociceptors. These sensory neurons can release many neuropeptides, and some can attract or activate innate immune cells (mast cells, DC) and T lymphocytes. The production of these neuropeptides by nociceptors may, thus, affect the first steps of the immune response, altering the efficacy of adaptive immune responses. We are analyzing the role played by nociceptors in the activation and recruitment of innate immune cells in the skin after tissue damage or infection, and in the generation of adaptive immune responses. In particular, we are using genetic mouse models in which the innervation of the skin by primary sensory neurons is either defective or completely abolished. These mice have impaired sensitivity to injury and inflammation-induced pain and are valuable tools for investigating the role of sensory nerves in the immune response in vivo.
We are monitoring the impact of the lack of skin innervation by nociceptive sensory neurons on the activation and recruitment of immune cells in the skin and cutaneous lymph node (LN) of mice after injury and infection.
We found that these neurons are important for the regulation of both innate and adaptive immune responses. We have also identified a molecule, produced by a subset of neurons which regulates skin inflammation and tissue repair. The mechanisms involved are under investigation.

2) Role of the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS) on the regulation of tissue-specific inflammatory responses.
Following stress, infection or inflammation, stimulation of the HPA axis and the sympathetic nervous system (SNS) induces the adrenal gland to release epinephrine and glucocorticoids into the bloodstream. Nerve fibers from the SNS also release the neurotransmitter norepinephrine into lymphoid organs and tissues. These mediators can stimulate adrenergic receptors (AR) and glucocorticoid receptors (GR) on leukocytes. We are studying the role of these receptors in innate lymphoid cells (ILCs) and myeloid cells. We have already shown that host resistance to endotoxic shock requires the neuroendocrine regulation of group 1 ILCs through the glucocorticoid receptor (Quatrini at al. 2017) revealing a novel strategy of host protection from immunopathology.


Our results show that the immune response is regulated by mediators produced by the nervous system. We are further deciphering the cellular and molecular mechanisms involved.

Final results

Our studies are providing new insight into the mechanisms by which the nervous and immune systems cooperate to ensure a controlled and appropriate response to pathological challenges, to restore homeostasis. We expect that this study will enable us to propose new innovative therapeutic strategies.