Stress Inhibits Hair Growth in Mice by Induction of Premature Catagen Development and Deleterious Perifollicular Inflammatory Events via Neuropeptide Substance P-Dependent Pathways

Abstract

It has been much disputed whether or not stress can cause hair loss (telogen effluvium) in a clinically relevant manner. Despite the paramount psychosocial importance of hair in human society, this central, yet enigmatic and controversial problem of clinically applied stress research has not been systematically studied in appropriate animal models. We now show that psychoemotional stress indeed alters actual hair follicle (HF) cycling in vivo, ie, prematurely terminates the normal duration of active hair growth (anagen) in mice. Further, inflammatory events deleterious to the HF are present in the HF environment of stressed mice (perifollicular macrophage cluster, excessive mast cell activation). This provides the first solid pathophysiological mechanism for how stress may actually cause telogen effluvium, ie, by hair cycle manipulation and neuroimmunological events that combine to terminate anagen. Furthermore, we show that most of these hair growth-inhibitory effects of stress can be reproduced by the proteotypic stress-related neuropeptide substance P in nonstressed mice, and can be counteracted effectively by co-administration of a specific substance P receptor antagonist in stressed mice. This offers the first convincing rationale how stress-induced hair loss in men may be pharmacologically managed effectively.

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

“…3 As depicted in Figure 3A, we observed a significant increase in the progression of the hair cycle from a predominance of anagen VI follicles in non-stressed control mice toward a predominance of early catagen follicles in stressed mice. Figure 2I displays such a premature hair cycle stage in stressed mice.…”

“…Moreover, BMP4 is able to induce SP expression in naive neurons 54,55 thereby contributing to the increase of SP ϩ neurons observed in stressed catagen skin. 3 Apart from directly inducing apoptosis of hair follicle keratinocytes, p75NTR also down-regulates growth-promoting keratinocyte growth factor (KGF) effects on keratinocyte proliferation and differentiation by down-regulation of the respective high-affinity receptor fibroblast growth factor receptor (FGFR-2) receptor. 56 KGF also provides significant cytoprotection to growing hair follicles in the murine model of chemotherapy 57 and may also do so under inflammatory conditions.…”

“…At the same time, it induces neurogenic inflammation characterized by perifollicular mast cell degranulation and accumulation of antigen-presenting cells, eg, activated macrophages. 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. …”

“…At the same time, it induces neurogenic inflammation characterized by perifollicular mast cell degranulation and accumulation of antigen-presenting cells, eg, activated macrophages. 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.…”

“…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).…”