Advertisement

Stress and the Hair Follicle

Exploring the Connections
  • Vladimir A. Botchkarev
    Correspondence
    Address reprint requests to Vladimir A. Botchkarev, M.D., Ph.D., Department of Dermatology, Boston University School of Medicine, 609 Albany St., Boston, MA 02118
    Affiliations
    Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts
    Search for articles by this author
      All living organisms are constantly challenged by a diversity of exogenous (environmental, psychological, social) and endogenous stimuli or stressors, which induce general or local biological responses to protect or adapt the organism to the stressor(s).
      • Selye H
      Forty years of stress research: principal remaining problems and misconceptions.
      The systemic biological response of the organism to exogenous stressors (or classical stress response) includes activation of the hypothalamic-pituitary-adrenal axis and release of hypothalamic corticotropin-releasing hormone (CRH) that activates pituitary CRH receptors (CRH-R) followed by the production and release of proopiomelanocortin-derived peptides and adrenal hormones.
      • Welch WJ
      Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease.
      • Pacak K
      • Palkovits M
      Stressor specificity of central neuroendocrine responses: implications for stress-related disorders.
      Systemic stress response also includes the modulation of the autonomic nervous and immune systems: neuroendocrine hormones and neurotransmitters influence the function of the immune system that reciprocally regulate CNS functions through cytokine release.
      • Webster JI
      • Tonelli L
      • Sternberg EM
      Neuroendocrine regulation of immunity.

      Skin as a Target for Systemic and Local Stress Responses

      Skin is an organ that covers and protects body from environmental (physical, chemical, or biological) stressors, which include temperature, ultraviolet radiation, mechanical trauma, biological insults, and chemicals. Skin is richly innervated by sensory nerves
      • Lewin GR
      Neurotrophins and the specification of neuronal phenotype.
      • Ansel JC
      • Armstrong CA
      • Song I
      • Quinlan KL
      • Olerud JE
      • Caughman SW
      • Bunnett NW
      Interactions of the skin and nervous system.
      that transmit information about the effects caused by environmental stressors to the central nervous system to develop the systemic response of the organism appropriate to its external environment. In turn, the hormones secreted during the systemic stress response and neurotransmitters of the autonomic nerve fibers innervating skin may target skin cells and modulate or affect their functions, depending on circumstances.
      • Slominski A
      • Wortsman J
      Neuroendocrinology of the skin.
      Data obtained during the last decade suggest that the major molecular components that mediate the systemic response to environmental stressors (CRH and proopiomelanocortin peptides), as well as neurotransmitters and cytokines are also expressed in the skin.
      • Slominski A
      • Wortsman J
      Neuroendocrinology of the skin.
      • Luger TA
      • Scholzen T
      • Brzoska T
      • Becher E
      • Slominski A
      • Paus R
      Cutaneous immunomodulation and coordination of skin stress responses by alpha-melanocyte-stimulating hormone.
      • Slominski AT
      • Botchkarev V
      • Choudhry M
      • Fazal N
      • Fechner K
      • Furkert J
      • Krause E
      • Roloff B
      • Sayeed M
      • Wei E
      • Zbytek B
      • Zipper J
      • Wortsman J
      • Paus R
      Cutaneous expression of CRH and CRH-R. Is there a “skin stress response system?”.
      • Slominski A
      • Wortsman J
      • Luger T
      • Paus R
      • Solomon S
      Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress.
      Specifically, it is shown that epidermal keratinocytes, fibroblasts, mast cells, and immune cells express CRH-R1, whereas CRH protein is expressed in keratinocytes and dermal nerve fibers.
      • Roloff B
      • Fechner K
      • Slominski A
      • Furkert J
      • Botchkarev VA
      • Bulfone-Paus S
      • Zipper J
      • Krause E
      • Paus R
      Hair cycle-dependent expression of corticotropin-releasing factor and CRF receptors in murine skin.
      • Slominski A
      • Wortsman J
      • Pisarchik A
      • Zbytek B
      • Linton EA
      • Mazurkiewicz JE
      • Wei ET
      Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors.
      The proopiomelanocortin peptides (ACTH, α-MSH, β-endorphin) have also been detected in keratinocytes, melanocytes, and Langerhans cells.
      • Paus R
      • Botchkarev VA
      • Botchkareva NV
      • Mecklenburg L
      • Luger T
      • Slominski A
      The skin POMC system (SPS). Leads and lessons from the hair follicle.
      • Botchkarev VA
      • Botchkareva NV
      • Slominski A
      • Roloff B
      • Luger T
      • Paus R
      Developmentally regulated expression of alpha-MSH and MC-1 receptor in C57BL/6 mouse skin suggests functions beyond pigmentation.
      • Grando SA
      Biological functions of keratinocyte cholinergic receptors.
      • Slominski A
      • Botchkareva NV
      • Botchkarev VA
      • Chakraborty A
      • Luger T
      • Uenalan M
      • Paus R
      ACTH production in C57BL/6 mouse skin.
      • Slominski A
      • Botchkareva NV
      • Botchkarev VA
      • Chakraborty A
      • Luger T
      • Uenalan M
      • Paus R
      Hair cycle-dependent production of ACTH in mouse skin.
      Neurohormones, cytokines, and neurotransmitters secreted by the major structural components of the skin (keratinocytes, melanocytes, fibroblasts, immune and endothelial cells, nerve fibers) form a molecular network of signals that is activated during cutaneous response to different environmental stimuli.
      • Slominski A
      • Wortsman J
      • Luger T
      • Paus R
      • Solomon S
      Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress.
      Therefore, together with the systemic stress response, environmental stressors may also induce the stress response inside of the skin, which may operate as a local equivalent of the hypothalamic-pituitary-adrenal axis.
      • Slominski A
      • Wortsman J
      • Luger T
      • Paus R
      • Solomon S
      Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress.
      Numerous indications suggest that both systemic and local responses to stressors may have roles in the onset or exacerbation of a variety of skin diseases.
      • Kimyai-Asadi A
      • Usman A
      The role of psychologic stress in skin disease.
      Psychological stress is now considered as an important etiological factor in the onset of psoriasis, atopic dermatitis, pruritus, and urticaria.
      • Kimyai-Asadi A
      • Usman A
      The role of psychologic stress in skin disease.
      Sensory neuropeptides and neurotransmitters released by sensory and autonomic nerve fibers that innervate the skin can directly modulate functions of keratinocytes, melanocytes, Langerhans cells, mast cells, endothelial cells, and immune cells.
      • Grando SA
      Biological functions of keratinocyte cholinergic receptors.
      • Scholzen T
      • Armstrong CA
      • Bunnett NW
      • Luger TA
      • Olerud JE
      • Ansel JC
      Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems.
      • Schallreuter KU
      Epidermal adrenergic signal transduction as part of the neuronal network in the human epidermis.
      • Misery L
      The neuro-immuno-cutaneous system and ultraviolet radiation.
      Among the molecules substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, somatostatin, noradrenaline, and acetylcholine have been reported to effectively modulate skin and immune cell functions such as cell proliferation, cytokine production, or antigen presentation under normal and pathological conditions.
      • Grando SA
      Biological functions of keratinocyte cholinergic receptors.
      • Scholzen T
      • Armstrong CA
      • Bunnett NW
      • Luger TA
      • Olerud JE
      • Ansel JC
      Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems.
      • Schallreuter KU
      Epidermal adrenergic signal transduction as part of the neuronal network in the human epidermis.
      • Misery L
      The neuro-immuno-cutaneous system and ultraviolet radiation.
      • Scholzen TE
      • Brzoska T
      • Kalden DH
      • O'Reilly F
      • Armstrong CA
      • Luger TA
      • Ansel JC
      Effect of ultraviolet light on the release of neuropeptides and neuroendocrine hormones in the skin: mediators of photodermatitis and cutaneous inflammation.
      This further proves the concept that skin serves as an important target for systemic and local stress responses.

      Neurohormones, Neuropeptides, and Neurotransmitters—Are They Capable of Influencing Hair Growth?

      Hair follicle is a skin appendage that shows cyclic activity in postnatal life with periods of active growth and hair formation (anagen), rapid apoptosis-driven involution (catagen), and relative resting (telogen).
      • Paus R
      Control of the hair cycle and hair diseases as cycling disorders.
      • Paus R
      • Cotsarelis G
      The biology of hair follicles.
      • Stenn KS
      • Paus R
      Control of hair follicle cycling.
      Hair follicle transition between distinct hair cycle stages is governed by epithelial-mesenchymal interactions between the follicular keratinocytes and dermal papilla fibroblasts.
      • Paus R
      • Cotsarelis G
      The biology of hair follicles.
      • Stenn KS
      • Paus R
      Control of hair follicle cycling.

      Botchkarev VA, Kishimoto J: Molecular control of epithelial-mesenchymal interactions during the hair follicle cycling. J Invest Dermatol Symp Proc (in press)

      Growth factors forming a molecular network of signals that the epithelium and the mesenchyme send to each other during the hair cycle belong to the Wnt, transforming growth factor-β/bone morphogenetic protein (BMP), Hedgehog, fibroblast growth factor, Notch, epidermal growth factor, tumor necrosis factor, and neurotrophin families.
      • Paus R
      • Cotsarelis G
      The biology of hair follicles.
      • Stenn KS
      • Paus R
      Control of hair follicle cycling.

      Botchkarev VA, Kishimoto J: Molecular control of epithelial-mesenchymal interactions during the hair follicle cycling. J Invest Dermatol Symp Proc (in press)

      Accumulating evidence of the data suggests that neurohormones, neurotransmitters, and cytokines released during the stress response may also significantly influence the hair cycle.
      • Paus R
      • Botchkarev VA
      • Botchkareva NV
      • Mecklenburg L
      • Luger T
      • Slominski A
      The skin POMC system (SPS). Leads and lessons from the hair follicle.
      • Paus R
      • Peters EM
      • Eichmuller S
      • Botchkarev VA
      Neural mechanisms of hair growth control.
      Actively growing hair follicles in mice and humans show expression of CRH-R1 and melanocortin-1 receptor (MC-1R) in the follicular epithelium and mesenchyme.
      • Roloff B
      • Fechner K
      • Slominski A
      • Furkert J
      • Botchkarev VA
      • Bulfone-Paus S
      • Zipper J
      • Krause E
      • Paus R
      Hair cycle-dependent expression of corticotropin-releasing factor and CRF receptors in murine skin.
      • Paus R
      • Botchkarev VA
      • Botchkareva NV
      • Mecklenburg L
      • Luger T
      • Slominski A
      The skin POMC system (SPS). Leads and lessons from the hair follicle.
      • Botchkarev VA
      • Botchkareva NV
      • Slominski A
      • Roloff B
      • Luger T
      • Paus R
      Developmentally regulated expression of alpha-MSH and MC-1 receptor in C57BL/6 mouse skin suggests functions beyond pigmentation.
      Administration of ACTH into murine telogen skin causes mast cell degranulation and activation of hair growth in resting hair follicles.
      • Paus R
      • Maurer M
      • Slominski A
      • Czarnetzki BM
      Mast cell involvement in murine hair growth.
      However, ACTH treatment also induces premature hair follicle anagen-catagen transition.
      • Maurer M
      • Fischer E
      • Handjiski B
      • von Stebut E
      • Algermissen B
      • Bavandi A
      • Paus R
      Activated skin mast cells are involved in murine hair follicle regression (catagen).
      Similarly to the stress-induced thymic involution, glucocorticoids stimulate apoptosis in the follicular epithelium leading to premature hair follicle involution.
      • Paus R
      • Handjiski B
      • Czarnetzki BM
      • Eichmüller S
      A murine model for inducing and manipulating hair follicle regression (catagen): effects of dexamethasone and cyclosporin A.
      Thus, the effects of neurohormones on hair follicle growth seem to be more complex than previously appreciated and strongly depend of hair cycle stage.
      The hair follicle is richly innervated by sensory and autonomic nerve fibers. In murine dorsal skin, nerve fibers that innervate hair follicles form two networks: around the distal outer root sheath in the subepidermal dermis (follicular network A) and around the outer root sheath between the sebaceous gland and the insertion point of the arrector pili muscle (follicular network B).
      • Botchkarev VA
      • Eichmüller S
      • Johansson O
      • Paus R
      Hair cycle-dependent plasticity of skin and hair follicle innervation in normal murine skin.
      • Botchkarev VA
      • Peters EM
      • Botchkareva NV
      • Maurer M
      • Paus R
      Hair cycle-dependent changes in adrenergic skin innervation, and hair growth modulation by adrenergic drugs.
      • Peters EM
      • Botchkarev VA
      • Botchkareva NV
      • Tobin DJ
      • Paus R
      Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides.
      The follicular network A consists of unmyelinated C-fibers expressing such neuropeptides as substance P, calcitonin gene-related peptide, peptide-histidine-methionin (PHM), and the enzymes choline acetyltransferase and tyrosine hydroxylase.
      • Botchkarev VA
      • Peters EM
      • Botchkareva NV
      • Maurer M
      • Paus R
      Hair cycle-dependent changes in adrenergic skin innervation, and hair growth modulation by adrenergic drugs.
      • Peters EM
      • Botchkarev VA
      • Botchkareva NV
      • Tobin DJ
      • Paus R
      Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides.
      Follicular network B consists of a collar of longitudinal and circular nerve fibers arranged in the manner of a palisade around the outer root sheath of the hair follicle. These nerve fibers function as slowly adapting mechanoreceptors and show expression of calcitonin gene-related peptide and choline acetyltransferase.
      • Lewin GR
      Neurotrophins and the specification of neuronal phenotype.
      • Botchkarev VA
      • Peters EM
      • Botchkareva NV
      • Maurer M
      • Paus R
      Hair cycle-dependent changes in adrenergic skin innervation, and hair growth modulation by adrenergic drugs.
      • Peters EM
      • Botchkarev VA
      • Botchkareva NV
      • Tobin DJ
      • Paus R
      Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides.
      Together they fill the space between the sebaceous gland and the hair follicle epithelium adjacent to the bulge region and distal to the arrector pili muscle. In human hair follicles, substance P-positive nerves are also found in the dermal papilla.
      • Hordinsky M
      • Ericson M
      • Snow D
      • Boeck C
      • Lee WS
      Peribulbar innervation and substance P expression following nonpermanent injury to the human scalp hair follicle.
      The hair follicle bulge region contains a population of putative hair follicle stem cells.
      • Cotsarelis G
      • Sun TT
      • Lavker RM
      Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis.
      • Cotsarelis G
      • Kaur P
      • Dhouailly D
      • Hengge U
      • Bickenbach J
      Epithelial stem cells in the skin: definition, markers, localization and functions.
      • Cotsarelis G
      • Millar SE
      Towards a molecular understanding of hair loss and its treatment.
      A close localization of sensory and autonomic nerve fibers and hair follicle bulge raises a possibility that neuropeptides and neurotransmitters may influence stem cells or their progeny and modulate hair cycle.
      • Paus R
      • Peters EM
      • Eichmuller S
      • Botchkarev VA
      Neural mechanisms of hair growth control.
      Indeed, bulge keratinocytes show expression of β2-adrenoreceptors and neurokinin-1 receptor
      • Botchkarev VA
      • Peters EM
      • Botchkareva NV
      • Maurer M
      • Paus R
      Hair cycle-dependent changes in adrenergic skin innervation, and hair growth modulation by adrenergic drugs.
      (Botchkarev et al, unpublished observations). Treatment of telogen mice by substance P or by noradrenaline-depleting agents lead to stimulation of hair growth, whereas substance P administration into anagen skin results in premature catagen development.
      • Maurer M
      • Fischer E
      • Handjiski B
      • von Stebut E
      • Algermissen B
      • Bavandi A
      • Paus R
      Activated skin mast cells are involved in murine hair follicle regression (catagen).
      • Paus R
      • Heinzelmann T
      • Schultz KD
      • Furkert J
      • Fechner K
      • Czarnetzki BM
      Hair growth induction by substance P.
      Recent data suggest that denervation of murine skin leads to down-regulation of expression of hair keratin genes.
      • Fundin BT
      • Rice FL
      • Ernfors P
      Patterned gene programs and target remodeling following axotomy at a major site for sensory innervation.
      Taken together, these data suggest that neurohormones, neuropeptides, and neurotransmitters may significantly influence cyclic activity of the hair follicle further supporting the hypothesis that hair follicles represent an important target for stressors.

      Toward Understanding the Molecular Mechanisms of the Hair Follicle Response to Stressors

      There are several indications in the literature suggesting that severe psycho-emotional stress may cause the onset of alopecia areata.
      • Thies W
      Über die Morphologie des vegetativen Nervensystems in der menschlichen Haut nebst Untersuchung über neuropathologische Veränderungen bei verschiedenen Hautkrankheiten.
      • Hordinsky MK
      • Ericson ME
      Relationship between follicular nerve supply and alopecia.
      • Katsarou-Katsari A
      • Singh LK
      • Theoharides TC
      Alopecia areata and affected skin CRH receptor upregulation induced by acute emotional stress.
      Also, it has been long debated whether or not environmental or psychosocial stressors can significantly influence hair growth.
      • Paus R
      • Botchkarev VA
      • Botchkareva NV
      • Mecklenburg L
      • Luger T
      • Slominski A
      The skin POMC system (SPS). Leads and lessons from the hair follicle.
      • Weigand DA
      Alopecias—diagnostic and pathogenetic considerations.
      • Helm TN
      Evaluation of alopecia.
      • Spencer LV
      • Callen JP
      Hair loss in systemic disease.
      • Gauthier Y
      Stress and skin: experimental approach.
      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).
      • Arck PC
      • Handjiski B
      • Hagen E
      • Joachim R
      • Klapp BF
      • Paus R
      Indications for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P.
      Investigators showed that in mice audiogenic (sonic) stressor induces appearance of apoptotic cells in resting hair follicles and inhibits keratinocyte proliferation.
      • Arck PC
      • Handjiski B
      • Hagen E
      • Joachim R
      • Klapp BF
      • Paus R
      Indications for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P.
      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 γδ T cells.
      • Arck PC
      • Handjiski B
      • Hagen E
      • Joachim R
      • Klapp BF
      • Paus R
      Indications for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P.
      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.
      • Arck PC
      • Handjiski B
      • Hagen E
      • Joachim R
      • Klapp BF
      • Paus R
      Indications for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P.
      In the article published in the current issue of The American Journal of Pathology, Arck and colleagues
      • Arck PC
      • Handjiski B
      • Peters EMJ
      • Peter AS
      • Hagen E
      • Fisher A
      • Klapp BF
      • Paus R
      Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.
      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.
      • Arck PC
      • Handjiski B
      • Peters EMJ
      • Peter AS
      • Hagen E
      • Fisher A
      • Klapp BF
      • Paus R
      Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.
      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 colleagues
      • Arck PC
      • Handjiski B
      • Peters EMJ
      • Peter AS
      • Hagen E
      • Fisher A
      • Klapp BF
      • Paus R
      Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.
      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 cycle
      • Botchkarev VA
      • Eichmuller S
      • Peters EM
      • Pietsch P
      • Johansson O
      • Maurer M
      • Paus R
      A simple immunofluorescence technique for simultaneous visualization of mast cells and nerve fibers reveals selectivity and hair cycle—dependent changes in mast cell-nerve fiber contacts in murine skin.
      and also in a variety of pathological situations including wound healing, atopic dermatitis, and psoriasis.
      • Ansel JC
      • Armstrong CA
      • Song I
      • Quinlan KL
      • Olerud JE
      • Caughman SW
      • Bunnett NW
      Interactions of the skin and nervous system.
      • Ansel JC
      • Kaynard AH
      • Armstrong CA
      • Olerud J
      • Bunnett N
      • Payan D
      Skin-nervous system interactions.
      . Substance P is a potent mast cell secretagogue and may stimulate the release of proinflammatory cytokines such as tumor necrosis factor-α by mast cells.
      • Scholzen T
      • Armstrong CA
      • Bunnett NW
      • Luger TA
      • Olerud JE
      • Ansel JC
      Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems.
      • Scholzen TE
      • Brzoska T
      • Kalden DH
      • O'Reilly F
      • Armstrong CA
      • Luger TA
      • Ansel JC
      Effect of ultraviolet light on the release of neuropeptides and neuroendocrine hormones in the skin: mediators of photodermatitis and cutaneous inflammation.
      Importantly, CRH released during the stress response is also capable of inducing mast cell degranulation.
      • Theoharides TC
      • Singh LK
      • Boucher W
      • Pang X
      • Letourneau R
      • Webster E
      • Chrousos G
      Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its pro-inflammatory effects.
      • Singh LK
      • Pang X
      • Alexacos N
      • Letourneau R
      • Theoharides TC
      Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: a link to neurogenic skin disorders.
      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 colleagues
      • Arck PC
      • Handjiski B
      • Peters EMJ
      • Peter AS
      • Hagen E
      • Fisher A
      • Klapp BF
      • Paus R
      Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.
      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 colleagues
      • Arck PC
      • Handjiski B
      • Peters EMJ
      • Peter AS
      • Hagen E
      • Fisher A
      • Klapp BF
      • Paus R
      Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.
      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.

      References

        • Selye H
        Forty years of stress research: principal remaining problems and misconceptions.
        Can Med Assoc J. 1976; 115: 53-56
        • Welch WJ
        Mammalian stress response: cell physiology, structure/function of stress proteins, and implications for medicine and disease.
        Physiol Rev. 1992; 72: 1063-1081
        • Pacak K
        • Palkovits M
        Stressor specificity of central neuroendocrine responses: implications for stress-related disorders.
        Endocrine Rev. 2001; 22: 502-548
        • Webster JI
        • Tonelli L
        • Sternberg EM
        Neuroendocrine regulation of immunity.
        Annu Rev Immunol. 2002; 20: 125-163
        • Lewin GR
        Neurotrophins and the specification of neuronal phenotype.
        Philos Trans R Soc Lond B Biol Sci. 1996; 351: 405-411
        • Ansel JC
        • Armstrong CA
        • Song I
        • Quinlan KL
        • Olerud JE
        • Caughman SW
        • Bunnett NW
        Interactions of the skin and nervous system.
        J Invest Dermatol Symp Proc. 1997; 2: 23-26
        • Slominski A
        • Wortsman J
        Neuroendocrinology of the skin.
        Endocrine Rev. 2000; 21: 457-487
        • Luger TA
        • Scholzen T
        • Brzoska T
        • Becher E
        • Slominski A
        • Paus R
        Cutaneous immunomodulation and coordination of skin stress responses by alpha-melanocyte-stimulating hormone.
        Ann NY Acad Sci. 1998; 840: 381-394
        • Slominski AT
        • Botchkarev V
        • Choudhry M
        • Fazal N
        • Fechner K
        • Furkert J
        • Krause E
        • Roloff B
        • Sayeed M
        • Wei E
        • Zbytek B
        • Zipper J
        • Wortsman J
        • Paus R
        Cutaneous expression of CRH and CRH-R. Is there a “skin stress response system?”.
        Ann NY Acad Sci. 1999; 885: 287-311
        • Slominski A
        • Wortsman J
        • Luger T
        • Paus R
        • Solomon S
        Corticotropin releasing hormone and proopiomelanocortin involvement in the cutaneous response to stress.
        Physiol Rev. 2000; 80: 979-1020
        • Roloff B
        • Fechner K
        • Slominski A
        • Furkert J
        • Botchkarev VA
        • Bulfone-Paus S
        • Zipper J
        • Krause E
        • Paus R
        Hair cycle-dependent expression of corticotropin-releasing factor and CRF receptors in murine skin.
        FASEB J. 1998; 12: 287-297
        • Slominski A
        • Wortsman J
        • Pisarchik A
        • Zbytek B
        • Linton EA
        • Mazurkiewicz JE
        • Wei ET
        Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors.
        FASEB J. 2001; 15: 1678-1693
        • Paus R
        • Botchkarev VA
        • Botchkareva NV
        • Mecklenburg L
        • Luger T
        • Slominski A
        The skin POMC system (SPS). Leads and lessons from the hair follicle.
        Ann NY Acad Sci. 1999; 885: 350-363
        • Botchkarev VA
        • Botchkareva NV
        • Slominski A
        • Roloff B
        • Luger T
        • Paus R
        Developmentally regulated expression of alpha-MSH and MC-1 receptor in C57BL/6 mouse skin suggests functions beyond pigmentation.
        Ann NY Acad Sci. 1999; 885: 433-439
        • Grando SA
        Biological functions of keratinocyte cholinergic receptors.
        J Invest Dermatol Symp Proc. 1997; 2: 41-48
        • Slominski A
        • Botchkareva NV
        • Botchkarev VA
        • Chakraborty A
        • Luger T
        • Uenalan M
        • Paus R
        ACTH production in C57BL/6 mouse skin.
        Ann NY Acad Sci. 1999; 885: 448-450
        • Slominski A
        • Botchkareva NV
        • Botchkarev VA
        • Chakraborty A
        • Luger T
        • Uenalan M
        • Paus R
        Hair cycle-dependent production of ACTH in mouse skin.
        Biochim Biophys Acta. 1998; 1448: 147-152
        • Kimyai-Asadi A
        • Usman A
        The role of psychologic stress in skin disease.
        J Cutan Med Surg. 2001; : 140-145
        • Scholzen T
        • Armstrong CA
        • Bunnett NW
        • Luger TA
        • Olerud JE
        • Ansel JC
        Neuropeptides in the skin: interactions between the neuroendocrine and the skin immune systems.
        Exp Dermatol. 1998; 7: 81-96
        • Schallreuter KU
        Epidermal adrenergic signal transduction as part of the neuronal network in the human epidermis.
        J Invest Dermatol Symp Proc. 1997; 2: 37-40
        • Misery L
        The neuro-immuno-cutaneous system and ultraviolet radiation.
        Photodermatol Photoimmunol Photomed. 2000; 16: 78-81
        • Scholzen TE
        • Brzoska T
        • Kalden DH
        • O'Reilly F
        • Armstrong CA
        • Luger TA
        • Ansel JC
        Effect of ultraviolet light on the release of neuropeptides and neuroendocrine hormones in the skin: mediators of photodermatitis and cutaneous inflammation.
        J Invest Dermatol Symp Proc. 1999; 4: 55-60
        • Paus R
        Control of the hair cycle and hair diseases as cycling disorders.
        Curr Opin Dermatol. 1996; 3: 248-258
        • Paus R
        • Cotsarelis G
        The biology of hair follicles.
        N Engl J Med. 1999; 341: 491-498
        • Stenn KS
        • Paus R
        Control of hair follicle cycling.
        Physiol Rev. 2001; 81: 449-494
      1. Botchkarev VA, Kishimoto J: Molecular control of epithelial-mesenchymal interactions during the hair follicle cycling. J Invest Dermatol Symp Proc (in press)

        • Paus R
        • Peters EM
        • Eichmuller S
        • Botchkarev VA
        Neural mechanisms of hair growth control.
        J Invest Dermatol Symp Proc. 1997; 2: 61-68
        • Paus R
        • Maurer M
        • Slominski A
        • Czarnetzki BM
        Mast cell involvement in murine hair growth.
        Dev Biol. 1994; 163: 230-240
        • Maurer M
        • Fischer E
        • Handjiski B
        • von Stebut E
        • Algermissen B
        • Bavandi A
        • Paus R
        Activated skin mast cells are involved in murine hair follicle regression (catagen).
        Lab Invest. 1997; 77: 319-332
        • Paus R
        • Handjiski B
        • Czarnetzki BM
        • Eichmüller S
        A murine model for inducing and manipulating hair follicle regression (catagen): effects of dexamethasone and cyclosporin A.
        J Invest Dermatol. 1994; 103: 143-147
        • Botchkarev VA
        • Eichmüller S
        • Johansson O
        • Paus R
        Hair cycle-dependent plasticity of skin and hair follicle innervation in normal murine skin.
        J Comp Neurol. 1997; 386: 379-395
        • Botchkarev VA
        • Peters EM
        • Botchkareva NV
        • Maurer M
        • Paus R
        Hair cycle-dependent changes in adrenergic skin innervation, and hair growth modulation by adrenergic drugs.
        J Invest Dermatol. 1999; 113: 878-887
        • Peters EM
        • Botchkarev VA
        • Botchkareva NV
        • Tobin DJ
        • Paus R
        Hair-cycle-associated remodeling of the peptidergic innervation of murine skin, and hair growth modulation by neuropeptides.
        J Invest Dermatol. 2001; 116: 236-245
        • Hordinsky M
        • Ericson M
        • Snow D
        • Boeck C
        • Lee WS
        Peribulbar innervation and substance P expression following nonpermanent injury to the human scalp hair follicle.
        J Invest Dermatol Symp Proc. 1999; 4: 316-319
        • Cotsarelis G
        • Sun TT
        • Lavker RM
        Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis.
        Cell. 1990; 61: 1329-1337
        • Cotsarelis G
        • Kaur P
        • Dhouailly D
        • Hengge U
        • Bickenbach J
        Epithelial stem cells in the skin: definition, markers, localization and functions.
        Exp Dermatol. 1999; 8: 80-88
        • Cotsarelis G
        • Millar SE
        Towards a molecular understanding of hair loss and its treatment.
        Trends Mol Med. 2001; 7: 293-301
        • Paus R
        • Heinzelmann T
        • Schultz KD
        • Furkert J
        • Fechner K
        • Czarnetzki BM
        Hair growth induction by substance P.
        Lab Invest. 1994; 71: 134-140
        • Fundin BT
        • Rice FL
        • Ernfors P
        Patterned gene programs and target remodeling following axotomy at a major site for sensory innervation.
        J Neurobiol. 2002; 53: 370-380
        • Thies W
        Über die Morphologie des vegetativen Nervensystems in der menschlichen Haut nebst Untersuchung über neuropathologische Veränderungen bei verschiedenen Hautkrankheiten.
        VI Mitteilung Alopecia areata Z Haut Geschlechtskr. 1960; 28: 47-52
        • Hordinsky MK
        • Ericson ME
        Relationship between follicular nerve supply and alopecia.
        Dermatol Clin. 1996; 14: 651-660
        • Katsarou-Katsari A
        • Singh LK
        • Theoharides TC
        Alopecia areata and affected skin CRH receptor upregulation induced by acute emotional stress.
        Dermatology. 2001; 203: 157-161
        • Weigand DA
        Alopecias—diagnostic and pathogenetic considerations.
        Nebr State Med J. 1969; 54: 26-37
        • Helm TN
        Evaluation of alopecia.
        JAMA. 1995; 273: 897-898
        • Spencer LV
        • Callen JP
        Hair loss in systemic disease.
        Dermatol Clin. 1987; 5: 565-570
        • Gauthier Y
        Stress and skin: experimental approach.
        Pathol Biol (Paris). 1996; 44: 882-887
        • Arck PC
        • Handjiski B
        • Hagen E
        • Joachim R
        • Klapp BF
        • Paus R
        Indications for a ‘brain-hair follicle axis (BHA)’: inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P.
        FASEB J. 2001; 15: 2536-2538
        • Arck PC
        • Handjiski B
        • Peters EMJ
        • Peter AS
        • Hagen E
        • Fisher A
        • Klapp BF
        • Paus R
        Stress inhibits hair growth in mice by induction of premature catagen development and deleterious perifollicular inflammatory events via neuropeptide substance P-dependent pathways.
        Am J Pathol. 2003; 162: 803-814
        • Botchkarev VA
        • Eichmuller S
        • Peters EM
        • Pietsch P
        • Johansson O
        • Maurer M
        • Paus R
        A simple immunofluorescence technique for simultaneous visualization of mast cells and nerve fibers reveals selectivity and hair cycle—dependent changes in mast cell-nerve fiber contacts in murine skin.
        Arch Dermatol Res. 1997; 289: 292-302
        • Ansel JC
        • Kaynard AH
        • Armstrong CA
        • Olerud J
        • Bunnett N
        • Payan D
        Skin-nervous system interactions.
        J Invest Dermatol. 1996; 106: 198-204
        • Theoharides TC
        • Singh LK
        • Boucher W
        • Pang X
        • Letourneau R
        • Webster E
        • Chrousos G
        Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its pro-inflammatory effects.
        Endocrinology. 1998; 139: 403-413
        • Singh LK
        • Pang X
        • Alexacos N
        • Letourneau R
        • Theoharides TC
        Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin, and substance P: a link to neurogenic skin disorders.
        Brain Behav Immun. 1999; 13: 225-239