Homeostatic pruning and activity of epidermal nerves are dysregulated in barrier-impaired skin during chronic itch development

Sonoko Takahashi,Masayuki Amagai,Manabu Nakayama,Azusa Ishida,Sotaro Ochiai,Hiroshi Kawasaki,Haruhiko Koseki,Akiharu Kubo,Takaharu Okada

doi:10.1038/s41598-019-44866-0

Abstract

The epidermal barrier is thought to protect sensory nerves from overexposure to environmental stimuli, and barrier impairment leads to pathological conditions associated with itch, such as atopic dermatitis (AD). However, it is not known how the epidermal barrier continuously protects nerves for the sensory homeostasis during turnover of the epidermis. Here we show that epidermal nerves are contained underneath keratinocyte tight junctions (TJs) in normal human and mouse skin, but not in human AD samples or mouse models of chronic itch caused by epidermal barrier impairment. By intravital imaging of the mouse skin, we found that epidermal nerve endings were frequently extended and retracted, and occasionally underwent local pruning. Importantly, the epidermal nerve pruning took place rapidly at intersections with newly forming TJs in the normal skin, whereas this process was disturbed during chronic itch development. Furthermore, aberrant Ca2+ increases in epidermal nerves were induced in association with the disturbed pruning. Finally, TRPA1 inhibition suppressed aberrant Ca2+ increases in epidermal nerves and itch. These results suggest that epidermal nerve endings are pruned through interactions with keratinocytes to stay below the TJ barrier, and that disruption of this mechanism may lead to aberrant activation of epidermal nerves and pathological itch.

Highlights

The skin barrier protects from invasions of external agents, and regulate immune and, most likely, nerve responses to them[1,2,3]
Even in the non-lesional skin of atopic dermatitis (AD) patients, there were areas where ZO-1 localization at tight junctions (TJs) was severely impaired, which is consistent with the previous reports[4,10], and nerves were found in the upper epidermal region (Fig. 1a; Supplementary Fig. 1a; Supplementary Movie 1)
Nerve fibers were not pruned at the transient ZO-1-Venus accumulations in the Spade epidermis (Supplementary Fig. 4d,e; Supplementary Movie 11). These results suggest that keratinocytes may interact with nerves at non-TJ sites to remodel the layout of epidermal nerve fibers, and that this process is disturbed in the Spade skin

Summary

Introduction

The skin barrier protects from invasions of external agents, and regulate immune and, most likely, nerve responses to them[1,2,3]. It has been suspected that epidermal nerves are aberrantly activated by overexposure to environmental stimuli during the development of AD due to the impaired protection by the epidermal barrier[2,3]. For the protection of epidermal nerves, the barrier structure should homeostatically cover over the nerves. Anatomical relationship between the barrier structures and epidermal nerves during turnover of the epidermis has not been demonstrated. We show that epidermal sensory nerves are contained underneath keratinocyte TJs in the normal skin, which appears to be at least partly due to nerve pruning at newly forming TJs. Our data suggest www.nature.com/scientificreports/. Www.nature.com/scientificreports that during the development of chronic itch caused by epidermal barrier impairment, this dynamic anatomical relationship is disrupted, and epidermal nerves are aberrantly activated

Methods

Results

Conclusion