Neuro-immune interactions in allergic diseases: novel targets for therapeutics

Abstract

Recent studies have highlighted an emerging role for neuro-immune interactions in mediating allergic diseases. Allergies are caused by an overactive immune response to a foreign antigen. The peripheral sensory and autonomic nervous system densely innervates mucosal barrier tissues including the skin, respiratory tract and gastrointestinal (GI) tract that are exposed to allergens. It is increasingly clear that neurons actively communicate with and regulate the function of mast cells, dendritic cells, eosinophils, Th2 cells and type 2 innate lymphoid cells in allergic inflammation. Several mechanisms of cross-talk between the two systems have been uncovered, with potential anatomical specificity. Immune cells release inflammatory mediators including histamine, cytokines or neurotrophins that directly activate sensory neurons to mediate itch in the skin, cough/sneezing and bronchoconstriction in the respiratory tract and motility in the GI tract. Upon activation, these peripheral neurons release neurotransmitters and neuropeptides that directly act on immune cells to modulate their function. Somatosensory and visceral afferent neurons release neuropeptides including calcitonin gene-related peptide, substance P and vasoactive intestinal peptide, which can act on type 2 immune cells to drive allergic inflammation. Autonomic neurons release neurotransmitters including acetylcholine and noradrenaline that signal to both innate and adaptive immune cells. Neuro-immune signaling may play a central role in the physiopathology of allergic diseases including atopic dermatitis, asthma and food allergies. Therefore, getting a better understanding of these cellular and molecular neuro-immune interactions could lead to novel therapeutic approaches to treat allergic diseases.

Future research trends in understanding the mechanisms underlying allergic diseases for improved patient care

“…It is becoming increasingly clear that immune cells do not act alone and that cross talk and reciprocal regulation between neural and immune systems are essential in the pathophysiology of allergic diseases including allergic asthma, atopic dermatitis, and food allergies. 55,56 Immune and neuronal cell types are found in large numbers at skin and mucosal barrier surfaces and are in close contact with each other forming a neuronal-immune cell network. [57][58][59][60] Both immune and neural cells detect and respond to environmental In addition to mediating allergic responses via immune responses, these proinflammatory mediators also directly activate sensory neurons that regulate itch, cough, sneezing, bronchoconstriction, and alterations in gastrointestinal motility.…”

“…59 On stimulation, sensory and autonomic neurons release neuropeptides and neurotransmitters such as substance P, neurokinin A, neuromedin U (NMU), calcitonin gene-related peptide, vasoactive intestinal peptide, acetylcholine, and norepinephrine that signal immune cells. 55 In the airways, calcitonin gene-related peptide is released by sensory nerves, which has been shown to inhibit dendritic cell maturation and allergen-specific T-cell responses. 61 In the gut, ILC2 cells were shown to express Nmur1, a receptor for the neuropeptide NMU.…”

Immune mediators and therapies for pruritus in atopic dermatitis and psoriasis

“…63 Sensory neurons released neuropeptides such as SP and CGRP that stimulate keratinocytes to secrete NGF, which in turn promotes proliferation of keratinocytes and hyperinnervation of sensory neurons. Keratinocytes and immune cells can release inflammatory mediators such as cytokines, histamine, and serotonin.…”

“…Many of these inflammatory mediators can activate sensory nerves to mediate itch in the skin. 63 Sensory neurons released neuropeptides such as SP and CGRP that stimulate keratinocytes to secrete NGF, which in turn promotes proliferation of keratinocytes and hyperinnervation of sensory neurons. SP and CGRP also act on Th2 cells to skew inflammation and act on mast cell to induce degranulation.…”

“…SP and CGRP also act on Th2 cells to skew inflammation and act on mast cell to induce degranulation. 63 The communication between skin and the nervous system is not restricted to the peripheral nervous system. Neurodegenerative diseases such as Parkinson's disease and dementia are more prevalent in elderly patients who met diagnostic criteria of AD.…”