Indications for a brain‐hair follicle axis: inhibition of keratinocyte proliferation and up‐regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P

Abstract

It has long been suspected that stress can cause hair loss, although convincing evidence of this has been unavailable. Here, we show that in mice sonic stress significantly increased the number of hair follicles containing apoptotic cells and inhibited intrafollicular keratinocyte proliferation in situ. Sonic stress also significantly increased the number of activated perifollicular macrophage clusters and the number of degranulated mast cells, whereas it down-regulated the number of intraepithelial gd T lymphocytes. These stress-induced immune changes could be mimicked by injection of the neuropeptide substance P in nonstressed mice and were abrogated by a selective substance P receptor antagonist in stressed mice. We conclude that stress can indeed inhibit hair growth in vivo, probably via a substance P-dependent activation of macrophages and/or mast cells in the context of a brain-hair follicle axis.

Neurogenic Inflammation in Stress-Induced Termination of Murine Hair Growth Is Promoted by Nerve Growth Factor

“…3 The neuropeptide substance P (SP) was identified as a key mediator of stress-induced hair growth inhibition, since increased number of SP-immunreactive nerve fibers were present in the skin of stressed mice and hair growth inhibition could be blocked by SP-receptor antagonists. 1,3 This is in line with previous findings that SP is a potent hair growth modulator in mice, since significant changes in the SP skin concentration, as well as in the number of SP-positive sensory nerve fibers are associated with murine hair follicle cycling. 4,5 Taken together, these findings point to the existence of a "brain-hair follicle axis" as a key element in the hair follicle's response to stress, which constitutes a prerequisite for generalized hair loss (telogen effluvium).…”

“…Tryptase-releasing mast cells can be found in close proximity to PAR-2-expressing cells such as keratinocytes and dermal endothelial cells or C-fibers during inflammation, 70 and we previously reported an increase in SP ϩ nerve fibers in stressed mice and observed that neurogenic inflammation may be abrogated by application of the SP high-affinity neurokinin-1 (NK1) receptor. 1,3 In the present study, cervical and thoracal sensory neurons innervating the dorsal skin were identified by retrograde transport of a tracer dye, subsequently providing insights into SP expression in skinspecific sensory neurons.…”

“…Six-to 8-week-old female C57BL/6 mice were purchased from Charles River (Sulzfeld, Germany) since mice at this age show the most reliable and profound stress-response 1 and are in the telogen stage of the hair cycle. The animals were housed in community cages at the animal facilities of the Charité , Virchow Hospital (University Medicine Berlin, Germany) with 12-hour light periods, and were fed water and mouse chow ad libitum.…”

“…This mouse model provides new insights into the pathophysiology of stress-induced hair growth inhibition and permits exploration of various strategies for therapeutic intervention. 1,2 In this model, exposure to sonic stress inhibits the growth of a hair shaft producing (anagen) hair follicle by premature induction of hair follicle regression (catagen) and up-regulated keratinocyte apoptosis. At the same time, it induces neurogenic inflammation characterized by perifollicular mast cell degranulation and accumulation of antigen-presenting cells, eg, activated macrophages.…”

Stress-Induced Neurogenic Inflammation in Murine Skin Skews Dendritic Cells Towards Maturation and Migration

“…28 -31 Established mouse models to investigate the impact of psychological stress on skin homeostasis are nowadays accessible. 5,32,33 Here, our group and others use the exposure to sound stress, a stress model that has also become appreciated as a highly instructive tool for neuroimmunological stress research beyond the skin. 34 -37 We have now followed-up our previous observations on stress-induced neurogenic skin inflammation by focusing on DCs.…”