Abstract
Cutaneous nerves are increased in atopic dermatitis, and itch is a prominent symptom. We studied the functional interactions between eosinophils and nerves in human and mouse skin and in culture. We demonstrated that human atopic dermatitis skin has eosinophil granule proteins present in the same region as increased nerves. Transgenic mice in which interleukin-5 (IL-5) expression is driven by a keratin-14 (K14) promoter had many eosinophils in the epidermis, and the number of nerves was also significantly increased in the epidermis. In co-cultures, eosinophils dramatically increased branching of sensory neurons isolated from the dorsal root ganglia (DRG) of mice. This effect did not occur in DRG neurons co-cultured with mast cells or with dead eosinophils. Physical contact of the eosinophils with the neurons was not required, and the effect was not blocked by an antibody to nerve growth factor. DRG neurons express eotaxin-1, ICAM-1 and VCAM-1, which may be important in the recruitment, binding, and activation of eosinophils in the region of cutaneous nerves. These data indicate a pathophysiological role for eosinophils in cutaneous nerve growth in atopic dermatitis, and suggest they may present a therapeutic target in atopic dermatitis and other eosinophilic skin conditions with neuronal symptoms such as itch.
Highlights
Atopic dermatitis is characterized by itch, which greatly affects the quality of life of patients [Jacquet, 1904 and [1]]
Our data demonstrate for the first time that eosinophils can dramatically increase sensory neuron branching, and that this effect is important in eosinophilic skin diseases, such as atopic dermatitis
We found that there were more nerves in lesional versus non-lesional atopic dermatitis, which correlated with the amount and location of eosinophil granule proteins
Summary
Atopic dermatitis is characterized by itch, which greatly affects the quality of life of patients [Jacquet, 1904 and [1]]. The itch often begins before any lesions appear, and marks on the skin can be limited to excoriations, or scratches, made by the patient. Patients with atopic dermatitis experience itch instead of pain when tested with mechanical, electrical, low pH, or heat stimuli [2]. The sensory neurons that transmit itch are primary afferents whose cell bodies are in the dorsal root ganglia (DRG). These free nerve endings in the epidermis and upper dermis can be activated by a variety of stimuli, including proteases, neurotrophins, cytokines and other small molecules (reviewed in [3]). One potential mechanism is an increase in nerve endings in atopic dermatitis skin [4]. There are more nerve fibers in the papillary and upper dermis as disease progresses from clinically normal-appearing, or non-lesional, skin to active disease, or lesional, skin [5]
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