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Neuroendocrine Perspectives in Alopecia Areata: Does Stress Play a Role?

2009; Elsevier BV; Volume: 129; Issue: 6 Linguagem: Inglês

10.1038/jid.2009.111

1523-1747

Ralf Paus, Petra Arck,

RNA regulation and disease

Until recently, the popular notion that psychoemotional stress can have an impact on hair growth has been treated with skepticism and assigned to the realm of folklore by many authorities. Yet it has long been appreciated that episodes of alopecia areata (AA) have occurred after severely stressful life events (Reinhold, 1960Reinhold M. Relationship of stress to the development of symptoms in alopecia areata and chronic urticaria.Br Med J. 1960; 1: 846-849Crossref PubMed Scopus (31) Google Scholar; Whitlock, 1976Whitlock F.A. Psychophysiological aspects of skin disease.in: Major R.A. Problems in Dermatology. 1976Google Scholar). This has triggered debates about whether AA should be considered a psychosomatic disorder (Misery and Rousset, 2001Misery L. Rousset H. Is alopecia areata a psychosomatic disease?.Rev Med Interne. 2001; 22 ([in French]): 274-279Crossref PubMed Google Scholar; Willemsen et al., 2009Willemsen R. Vanderlinden J. Roseeuw D. Haentjens P. Increased history of childhood and lifetime traumatic events among adults with alopecia areata.J Am Acad Dermatol. 2009; 60: 388-393Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). Until recently, the popular notion that psychoemotional stress can have an impact on hair growth has been treated with skepticism and assigned to the realm of folklore by many authorities. Yet it has long been appreciated that episodes of alopecia areata (AA) have occurred after severely stressful life events (Reinhold, 1960Reinhold M. Relationship of stress to the development of symptoms in alopecia areata and chronic urticaria.Br Med J. 1960; 1: 846-849Crossref PubMed Scopus (31) Google Scholar; Whitlock, 1976Whitlock F.A. Psychophysiological aspects of skin disease.in: Major R.A. Problems in Dermatology. 1976Google Scholar). This has triggered debates about whether AA should be considered a psychosomatic disorder (Misery and Rousset, 2001Misery L. Rousset H. Is alopecia areata a psychosomatic disease?.Rev Med Interne. 2001; 22 ([in French]): 274-279Crossref PubMed Google Scholar; Willemsen et al., 2009Willemsen R. Vanderlinden J. Roseeuw D. Haentjens P. Increased history of childhood and lifetime traumatic events among adults with alopecia areata.J Am Acad Dermatol. 2009; 60: 388-393Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). A convincing cause–effect relationship has never been firmly established between perceived stress and AA onset, course, and/or severity. It is by no means trivial to reliably distinguish “stress” as a genuine disease trigger from disease-induced distress that, retrospectively and erroneously, may be identified by affected individuals as the “cause” of their hair loss (Whitlock, 1976Whitlock F.A. Psychophysiological aspects of skin disease.in: Major R.A. Problems in Dermatology. 1976Google Scholar; Hadshiew et al., 2004Hadshiew I.M. Foitzik K. Arck P.C. Paus R. Burden of hair loss: stress and the underestimated psychosocial impact of telogen effluvium and androgenetic alopecia.J Invest Dermatol. 2004; 123: 455-457Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). In fact, the concept that AA can be triggered by psychoemotional stress has been cast into doubt (van et al., 1992van der Steen P. Boezeman J. Duller P. Happle R. Can alopecia areata be triggered by emotional stress? An uncontrolled evaluation of 178 patients with extensive hair loss.Acta Derm Venereol. 1992; 72: 279-280PubMed Google Scholar; Brajac et al., 2003Brajac I. Tkalcic M. Dragojevi D.M. Gruber F. Roles of stress, stress perception and trait-anxiety in the onset and course of alopecia areata.J Dermatol. 2003; 30: 871-878Crossref PubMed Scopus (64) Google Scholar). With the increasing evidence that AA is a T-cell-dependent, organ-specific autoimmune disease, the genesis of which is a collapse of the hair follicle’s immune privilege (Paus et al., 2005Paus R. Nickoloff B.J. Ito T. A ‘hairy’ privilege.Trends Immunol. 2005; 26: 32-40Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, Gilhar et al., 2007Gilhar A. Paus R. Kalish R.S. Lymphocytes, neuropeptides, and genes involved in alopecia areata.J Clin Invest. 2007; 117: 2019-2027Crossref PubMed Scopus (212) Google Scholar), the “brain–skin connection” (Paus et al., 2006Paus R. Theoharides T.C. Arck P.C. Neuroimmunoendocrine circuitry of the ‘brain-skin connection.Trends Immunol. 2006; 27: 32-39Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar) has been neglected. However, the fact remains that cases have been reported—albeit rarely—in which psychoemotional stress has clearly preceded AA onset or relapse, perhaps most impressively in the form of alopecia deux in a husband-and-wife setting under conditions of shared emotional stress (Swift, 1961Swift S. Folie deux? Simultaneous alopecia areata in husband and wife.Arch Dermatol. 1961; 84: 932-934Crossref Scopus (6) Google Scholar; Zalka et al., 1994). Moreover, striking abnormalities in peptidergic innervation of lesional hair follicles have been identified in AA (Hordinsky and Ericson, 1996Hordinsky M.K. Ericson M.E. Relationship between follicular nerve supply and alopecia.Dermatol Clin. 1996; 14: 651-660Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). The expression of receptors for a key neuroendocrine stress mediator, corticotropin-releasing hormone, and of another classic mediator along the hypothalamic–pituitary–adrenal (HPA) stress-response axis, adrenocorticotropin, were reported to be upregulated in lesional hair follicles of small cohorts of patients (Katsarou-Katsari et al., 2001Katsarou-Katsari A. Singh L.K. Theoharides T.C. Alopecia areata and affected skin CRH receptor upregulation induced by acute emotional stress.Dermatology. 2001; 203: 157-161Crossref PubMed Scopus (71) Google Scholar; Kim et al., 2006Kim H.S. Cho D.H. Kim H.J. Lee J.Y. Cho B.K. Park H.J. Immunoreactivity of corticotropin-releasing hormone, adrenocorticotropic hormone and alpha-melanocyte-stimulating hormone in alopecia areata.Exp Dermatol. 2006; 15: 515-522Crossref PubMed Scopus (47) Google Scholar). This ambiguous picture makes it inevitable that investigators will turn to animal models for help. Indeed, it was in mice that the first solid evidence was at long last generated that perceived stress could exert surprisingly profound hair growth–inhibitory effects, including the premature induction of hair follicle regression (catagen), probably as a consequence of perifollicular neurogenic inflammation (Arck et al., 2001Arck P.C. Handjiski B. Hagen E. Joachim R. Klapp B.F. 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: 2536-2538PubMed Google Scholar, Arck et al., 2003Arck P.C. Handjiski B. Peters E.M. Peter A.S. Hagen E. Fischer A. et al.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: 803-814Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar; Aoki et al., 2003Aoki E. Shibasaki T. Kawana S. Intermittent foot shock stress prolongs the telogen stage in the hair cycle of mice.Exp Dermatol. 2003; 12: 371-377Crossref PubMed Scopus (31) Google Scholar; Katayama et al., 2007Katayama M. Aoki E. Suzuki H. Kawana S. Foot shock stress prolongs the telogen stage of the spontaneous hair cycle in a non-depilated mouse model.Exp Dermatol. 2007; 16: 553-560Crossref PubMed Scopus (26) Google Scholar). Subsequently, detailed work in mice has identified at least one plausible molecular stress-response pathway by which perceived stress can lead to hair growth inhibition, with key roles identified for nerve growth factor, substance P (SP) and the cognate receptors as central stress mediators, and mast cells as “central switchboards” of stress-induced perifollicular neurogenic inflammation (Arck et al., 2005Arck P.C. Handjiski B. Kuhlmei A. Peters E.M. Knackstedt M. Peter A. et al.Mast cell deficient and neurokinin-1 receptor knockout mice are protected from stress-induced hair growth inhibition.J Mol Med. 2005; 83: 386-396Crossref PubMed Scopus (65) Google Scholar; Peters et al., 2006Peters E.M. Arck P.C. Paus R. Hair growth inhibition by psychological stress: a mouse model for neural mechanisms in hair growth control.Exp Dermatol. 2006; 15: 1-13Crossref PubMed Scopus (97) Google Scholar). This body of work has established that psychoemotional stress can indeed negatively impact hair growth, at least in mice. What has not been resolved, however, are the following questions: (i) whether any of this is relevant for humans, (ii) whether perceived stress can also induce actual hair shaft shedding, leading to visible alopecia, in mice, and (iii) whether stress can trigger or aggravate AA (in mice or in humans). The recent observations that both nerve growth factor and SP are potent hair growth inhibitors for human hair and that SP causes the major histocompatibility complex class I–based immune privilege of the hair follicle to collapse (Peters et al., 2005Peters E.M. Hansen M.G. Overall R.W. Nakamura M. Pertile P. Klapp B.F. et al.Control of human hair growth by neurotrophins: brain-derived neurotrophic factor inhibits hair shaft elongation, induces catagen, and stimulates follicular transforming growth factor b2 expression.J Invest Dermatol. 2005; 124: 675-685Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Peters et al., 2007Peters E.M. Liotiri S. Bod E. Hagen E. Br T. Arck P.C. Paus R. Probing the effects of stress mediators on the human hair follicle: substance P holds central position.Am J Pathol. 2007; 171: 1872-1886Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar) suggest that the stress studies for mice summarized above are relevant to humans as well. However, convincing experimental evidence that AA—or any form of visible hair loss, for that matter—can be triggered by perceived stress remains to be published. It is in this area that the study by Zhang et al., 2009Zhang X. Yu M. Yu W. Weinberg J. Shapiro J. McElwee K.J. Development of alopecia areata is associated with higher central and peripheral hypothalamic–pituitary–adrenal tone in the skin graft induced C3H/HeJ mouse model.J Invest Dermatol. 2009; 129: 1527-1538Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, this issue) attains special relevance and importance—not only by adding a long-overdue facet to our incomplete understanding of AA pathogenesis but also for its bearing on general stress research and cutaneous neuroendocrinology. Given that psychoemotional contributions to AA in humans may be camouflaged by emotional responses to the hair loss itself, the authors elegantly aimed at teasing apart stress-response pathways in the context of AA by turning to the murine system, using the best established and most widely studied animal model, AA C3H/HeJ mice (Sun et al., 2008Sun J. Silva K.A. McElwee K.J. King Jr, L.E. Sundberg J.P. The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results.Exp Dermatol. 2008; 17: 793-805Crossref PubMed Scopus (51) Google Scholar). A key finding of the study by Zhang et al., 2009Zhang X. Yu M. Yu W. Weinberg J. Shapiro J. McElwee K.J. Development of alopecia areata is associated with higher central and peripheral hypothalamic–pituitary–adrenal tone in the skin graft induced C3H/HeJ mouse model.J Invest Dermatol. 2009; 129: 1527-1538Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar is that these mice have a significantly blunted systemic HPA response to acute physiological Psychological stress is important in alopecia areata.stress, along with a defective adaptation to repeated psychological stress. Further, highly active central and peripheral HPA activity and defective interactions between the HPA and hypothalamic–pituitary–gonadal endocrine axes were observed. Strikingly, HPA hormones, as well as cytokine expression in the skin, were modulated by perceived stress in these mice (Zhang et al., 2009Zhang X. Yu M. Yu W. Weinberg J. Shapiro J. McElwee K.J. Development of alopecia areata is associated with higher central and peripheral hypothalamic–pituitary–adrenal tone in the skin graft induced C3H/HeJ mouse model.J Invest Dermatol. 2009; 129: 1527-1538Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). When normal C3H/HeJ mice and those affected with skin graft–induced AA were subjected to light ether anesthesia (as a physiological stressor) or restraint stress (as a psychological stressor), they displayed a marked increase in HPA tone and activity compared with control mice, not only centrally but also peripherally in the skin and lymph nodes. These observations underscore the now firmly established concept that murine and human skin and hair follicles display fully functional peripheral equivalents of the central HPA axis (Ito et al., 2005Ito N. Kromminga A. Bettermann A. Takigawa M. Kees F. Straub R.H. et al.Human hair follicles display a functional equivalent of the hypothalamic–pituitary–adrenal axis and synthesize cortisol.FASEB J. 2005; 19: 1332-1334Crossref PubMed Scopus (374) Google Scholar; Slominski et al., 2004Slominski A. Pisarchik A. Tobin D.J. Mazurkiewicz J.E. Wortsman J. Differential expression of a cutaneous corticotropin-releasing hormone system.Endocrinology. 2004; 145: 941-950Crossref PubMed Scopus (131) Google Scholar, Slominski et al., 2007Slominski A. Wortsman J. Tuckey R.C. Paus R. Differential expression of HPA axis homolog in the skin.Mol Cell Endocrinol. 2007; 265–266: 143-149Crossref PubMed Scopus (194) Google Scholar). Moreover, these mice had significantly blunted corticosterone and adrenocorticotropin responses to the physiological stressor and a deficit in habituation to repeated exposure to the employed psychological stressor. Finally, a positive correlation of HPA hormone levels with T helper 1 cytokine levels in the skin was observed. The authors conclude that altered HPA activity may occur as a consequence of the immune response associated with AA. This elegant study in a well-defined mouse model of an AA-like disease clearly supports the concept that psychological stress is an important factor to be reckoned with in individuals prone to develop AA. It nicely complements earlier work by Siebenhaar et al., 2007Siebenhaar F. Sharov A.A. Peters E.M. Sharova T.Y. Syska W. Mardaryev A.N. et al.Substance P as an immunomodulatory neuropeptide in a mouse model for autoimmune hair loss (alopecia areata).J Invest Dermatol. 2007; 127: 1489-1497Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, who investigated the role of SP in AA mice. Those authors found that the number of intracutaneous SP-immunoreactive nerve fibers increased during early stages of AA development, associated with enhanced degranulation of perifollicular mast cells, followed by a decline in the number of SP-immunoreactive nerves and SP protein levels in advanced lesional skin. SP receptors (NK1) were expressed on CD8+ lymphocytes and macrophages that accumulated around affected hair follicles in AA. Moreover, Zhang et al., 2009Zhang X. Yu M. Yu W. Weinberg J. Shapiro J. McElwee K.J. Development of alopecia areata is associated with higher central and peripheral hypothalamic–pituitary–adrenal tone in the skin graft induced C3H/HeJ mouse model.J Invest Dermatol. 2009; 129: 1527-1538Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar highlighted the level of complexity of the brain–skin connection in health and disease that must be taken into consideration, especially when hair follicles and stress responses are involved (Peters et al., 2006Peters E.M. Arck P.C. Paus R. Hair growth inhibition by psychological stress: a mouse model for neural mechanisms in hair growth control.Exp Dermatol. 2006; 15: 1-13Crossref PubMed Scopus (97) Google Scholar; Arck et al., 2006Arck P.C. Slominski A. Theoharides T.C. Peters E.M. Paus R. Neuroimmunology of stress: skin takes center stage.J Invest Dermatol. 2006; 126: 1697-1704Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). As the authors appropriately acknowledge, their study does not yet answer the original question of whether psychoemotional stress can actually trigger AA. In fact, they hypothesize that the altered HPA activity seen in AA could well result from the chronic inflammatory events that characterize AA skin (Gilhar et al., 2007Gilhar A. Paus R. Kalish R.S. Lymphocytes, neuropeptides, and genes involved in alopecia areata.J Clin Invest. 2007; 117: 2019-2027Crossref PubMed Scopus (212) Google Scholar; Sun et al., 2008Sun J. Silva K.A. McElwee K.J. King Jr, L.E. Sundberg J.P. The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results.Exp Dermatol. 2008; 17: 793-805Crossref PubMed Scopus (51) Google Scholar). It is a reasonable hypothesis that endocrine and inflammatory events associated with AA, rather than stress associated with the negative image perception triggered by the disease, may account for the aberrant psychosocial traits noted in some (but by no means the majority of) patients. It now remains to be determined whether and how the HPA axis participates in the onset of disease. The C3H/HeJ mouse model provides a platform for testing therapeutic intervention strategies in AA (Sun et al., 2008Sun J. Silva K.A. McElwee K.J. King Jr, L.E. Sundberg J.P. The C3H/HeJ mouse and DEBR rat models for alopecia areata: review of preclinical drug screening approaches and results.Exp Dermatol. 2008; 17: 793-805Crossref PubMed Scopus (51) Google Scholar). Given the pivotal role of SP—in responses to stress as well as in AA—testing highly selective SP receptor antagonists in the context of AA may not only ameliorate AA but also dampen the highly active central and peripheral HPA activity seen in the disease, which may improve patients’ resistance to stress challenges. The current study leaves open the intriguing and important question of the extent to which intracutaneously generated stress mediators (whose production in AA-affected skin and subsequent release into the circulation may well be greatly enhanced) affect the central HPA axis and thus modulate systemic immune responses by HPA axis–associated mediators (Arck et al., 2009Arck P.C. Gilhar A. Bienenstock J. Paus R. The alchemy of immune privilege explored from a neuroimmunological perspective.Curr Opin Pharmacol. 2009; 8: 480-489Crossref Scopus (24) Google Scholar; Paus et al., 2006Paus R. Theoharides T.C. Arck P.C. Neuroimmunoendocrine circuitry of the ‘brain-skin connection.Trends Immunol. 2006; 27: 32-39Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). This question notwithstanding, Zhang et al., 2009Zhang X. Yu M. Yu W. Weinberg J. Shapiro J. McElwee K.J. Development of alopecia areata is associated with higher central and peripheral hypothalamic–pituitary–adrenal tone in the skin graft induced C3H/HeJ mouse model.J Invest Dermatol. 2009; 129: 1527-1538Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar) elegantly underscore how important it is to pursue systematically a neuroendocrinological and neuroimmunological perspective in inflammatory skin disease research. Systematic exploitation of murine in vivo models (e.g., Arck et al., 2003Arck P.C. Handjiski B. Peters E.M. Peter A.S. Hagen E. Fischer A. et al.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: 803-814Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar; Aoki et al., 2003Aoki E. Shibasaki T. Kawana S. Intermittent foot shock stress prolongs the telogen stage in the hair cycle of mice.Exp Dermatol. 2003; 12: 371-377Crossref PubMed Scopus (31) Google Scholar; Kaneko et al., 2003Kaneko K. Kawana S. Arai K. Shibasaki T. Corticotropin-releasing factor receptor type 1 is involved in the stress-induced exacerbation of chronic contact dermatitis in rats.Exp Dermatol. 2003; 12: 47-52Crossref PubMed Scopus (41) Google Scholar; Zhang et al., 2009Zhang X. Yu M. Yu W. Weinberg J. Shapiro J. McElwee K.J. Development of alopecia areata is associated with higher central and peripheral hypothalamic–pituitary–adrenal tone in the skin graft induced C3H/HeJ mouse model.J Invest Dermatol. 2009; 129: 1527-1538Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar) will promote our understanding of the underestimated and underinvestigated, but clinically important, intimate relationship among psychoemotional stress, intracutaneous neurogenic inflammation, and peripheral tissue stress responses. Analysis of the latter should include dissection of stress- and/or inflammation-associated changes in skin innervation and skin neurophysiology, for example, following available guidelines (Hendrix et al., 2008Hendrix S. Picker B. Liezmann C. Peters E.M. Skin and hair follicle innervation in experimental models: a guide for the exact and reproducible evaluation of neuronal plasticity.Exp Dermatol. 2008; 17: 214-227Crossref PubMed Scopus (33) Google Scholar). In addition, future studies on intracutaneous responses to perceived stress should include attempts to determine whether skin-derived neuroendocrine feedback signals can indeed affect the central nervous system and the secretory activities of central endocrine organs. The authors state no conflict of interest.