NEURO-IMMUNOLOGY in HEALTH and DISEASE
The nervous and immune systems are traditionally thought of as two quite autonomous entities and are therefore generally studied separately. However, accumulating evidence suggests that the two systems often function in an integrated and coordinated manner. The two systems share the ability to sense external and internal environmental threats, detect danger, and coordinate appropriate defenses. Mechanistically, these systems communicate through a common language of cell surface G protein coupled receptors and receptor tyrosine kinases that enables them to respond to the signals each produces. They further share a broad common “language” of cytokines, growth factors, and neuropeptides that contributes to major bidirectional communication, which is adaptive in some contexts1. Unexpectedly, such interaction can become maladaptive and contribute to disease pathophysiology in other settings, as I have shown to be the case in the context of allergic airway inflammation. To follow up on this unexpected biology, my lab will be devoted to deciphering how, when, and where neuro-immune interplay becomes maladaptive and to devise approaches to restore adaptive interactions.
My overarching hypothesis is that the nature of the interaction between the sensory and immune systems depends on the type of inflammation, the chronicity of the response, and the location of the insult and that it may result in a spectrum of different pathophysiological changes and diseases. We will devote immediate efforts to continue uncovering such interaction in various inflammatory contexts, such as allergy, itch, obesity and host-microbiota interaction.
AXIS 1 : Nociceptors detect allergens
In a mouse model of allergic airway inflammation, I recently showed that the vasoactive intestinal peptide (VIP) discharged from vagal sensory neurons drives CD4+ and ILC2 cells to release IL-5, which further activates these fibers. From this, I concluded that nociceptors, also known as sensory neurons, amplify adaptive immune responses in the lung in response to allergen exposure in sensitized animals. I further showed that local pharmacological silencing of nociceptors interrupts this pro-inflammatory signaling loop between neurons and immune cell.
Although I have elucidated some of the downstream neuroimmune signaling maintaining allergic inflammation, the specific mechanism by which an antigen initiates type 2 inflammation in the airway and at what point nociceptors are engaged, are uncertain. Are these entirely reliant on mast cell recognition of the antigen after sensitization? One other possibility is that nociceptors may be activated directly or indirectly by allergen exposure. Precedence for recognition of foreign materials by nociceptors comes from my host laboratory’s earlier work, which showed that nociceptors are directly activated through receptors recognizing formylated peptides expressed by bacteria1. One candidate that could mediate allergen recognition by nociceptors is the Fc Receptor (FcR).
For this axis, we aim to delineate the specific biology of FCεR1 on nociceptors by analyzing 1.1) the mediators and mechanism driving FCεR1 expression, 1.2) the neuronal circuit involved in allergen sensing, 1.3) the downstream mediators of FCεR1 signaling and 1.4) the physiological consequences of allergen sensing.