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There are several indications in the literature suggesting that severe psycho-emotional stress may cause the onset of alopecia areata.^40–42 Also, it has been long debated whether or not environmental or psychosocial stressors can significantly influence hair growth.^13,43–46 First systematic studies to address this intriguing question have been recently performed by Hair Research Laboratory of R. Paus (University of Hamburg, Hamburg, Germany) and a neuroimmunological group with strong focus on stress-triggered dysbalances of physiological homeostasis led by P. Arck (Humboldt University, Berlin, Germany).⁴⁷ Investigators showed that in mice audiogenic (sonic) stressor induces appearance of apoptotic cells in resting hair follicles and inhibits keratinocyte proliferation.⁴⁷ Furthermore, sonic stressor causes significant changes in skin immune system: increase of number of activated perifollicular macrophage cluster and mast cell degranulation, as well as down-regulation of intraepithelial  T cells.⁴⁷ Interestingly, these changes could be abrogated by administration of selective substance P receptor antagonist suggesting involvement of substance P in realization of hair follicle response to stressor.⁴⁷

In the article published in the current issue of The American Journal of Pathology, Arck and colleagues⁴⁸ follow- up their previous work and provide further evidence for existence of "brain-hair follicle axis." They show that audiogenic stress also induces significant changes in actively growing hair follicles and promotes their transition into the involution phase. Premature termination of hair follicle growth induced by stressor is associated with up-regulation of keratinocyte apoptosis, increased mast cell degranulation, and appearance of perifollicular inflammatory infiltrates of activated macrophages.⁴⁸ Furthermore, the authors show that most of these hair growth-inhibitory effects of stressor can be reproduced in nonaffected mice by administration of substance P, whereas substance P receptor antagonist reduces the stress-induced hair growth inhibition.

Interestingly, Arck and colleagues⁴⁸ describe the increase of close contacts between substance P-containing nerve fibers and mast cells in skin after stressor exposure. Mast cell-nerve associations in skin have been noticed previously during the normal hair cycle⁴⁹ and also in a variety of pathological situations including wound healing, atopic dermatitis, and psoriasis.^6,50 Substance P is a potent mast cell secretagogue and may stimulate the release of proinflammatory cytokines such as tumor necrosis factor-
by mast cells.^19,22 Importantly, CRH released during the stress response is also capable of inducing mast cell degranulation.^51,52 These data suggest that mast cells are important local modulators of the hair follicle response to stress exposure and raise a possibility to speculate that inhibitors of mast cell secretory activity may also be effective to prevent stress-induced hair growth alterations.

The exciting data presented by Arck and colleagues⁴⁸ also raises several intriguing questions about the mechanisms involved in the hair follicle response induced by audiogenic stressor. It seems interesting to define whether substance P plays a major role in mediating the effects of audiogenic stress on the hair follicle, or other components of the systemic and local stress response (CRH, proopiomelanocortin peptides, glucocorticoid hormones, autonomic neurotransmitters) are also involved in stress-associated hair growth inhibition. Also, the cellular targets for substance P in the hair follicle during the stress response remain to be determined. In addition, it seems to be logical to ask which apoptotic pathways are activated in hair follicle keratinocytes after stress exposure and whether or not audiogenic stress also stimulates apoptosis in hair follicle melanocytes. Most importantly, data presented by Arck and colleagues⁴⁸ provides a model of depilation-induced hair cycle as a tool for researchers to further investigate the molecular mechanisms of hair follicle response to stress exposure. Hopefully, use of this model would bring important new knowledge into our understanding of stress-induced hair loss and would help to design in the near future new approaches for the treatment of stress-associated hair growth disturbances.

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