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• W1972558580 abstract "Like few other organs, the skin is continuously exposed to multiple exogenous and endogenous stressors. Superimposed on this is the impact of psychological stress on skin physiology and pathology. Here, we review the “brain–skin connection,” which may underlie inflammatory skin diseases triggered or aggravated by stress, and we summarize relevant general principles of skin neuroimmunology and neuroendocrinology. Specifically, we portray the skin and its appendages as both a prominent target of key stress mediators (such as corticotropin-releasing hormone, ACTH, cortisol, catecholamines, prolactin, substance P, and nerve growth factor) and a potent source of these prototypic, immunomodulatory mediators of the stress responses. We delineate current views on the role of mast cell-dependent neurogenic skin inflammation and discuss the available evidence that the skin has established a fully functional peripheral equivalent of the hypothalamic–pituitary–adrenal axis as an independent, local stress response system. To cope with stress-induced oxidative damage, the skin and hair follicles also express melatonin, probably the most potent neuroendocrine antioxidant. Lastly, we outline major, as-yet unmet challenges in cutaneous stress research, particularly in the study of the cross-talk between peripheral and systemic responses to psychological stress and in the identification of promising molecular targets for therapeutic stress intervention. Like few other organs, the skin is continuously exposed to multiple exogenous and endogenous stressors. Superimposed on this is the impact of psychological stress on skin physiology and pathology. Here, we review the “brain–skin connection,” which may underlie inflammatory skin diseases triggered or aggravated by stress, and we summarize relevant general principles of skin neuroimmunology and neuroendocrinology. Specifically, we portray the skin and its appendages as both a prominent target of key stress mediators (such as corticotropin-releasing hormone, ACTH, cortisol, catecholamines, prolactin, substance P, and nerve growth factor) and a potent source of these prototypic, immunomodulatory mediators of the stress responses. We delineate current views on the role of mast cell-dependent neurogenic skin inflammation and discuss the available evidence that the skin has established a fully functional peripheral equivalent of the hypothalamic–pituitary–adrenal axis as an independent, local stress response system. To cope with stress-induced oxidative damage, the skin and hair follicles also express melatonin, probably the most potent neuroendocrine antioxidant. Lastly, we outline major, as-yet unmet challenges in cutaneous stress research, particularly in the study of the cross-talk between peripheral and systemic responses to psychological stress and in the identification of promising molecular targets for therapeutic stress intervention. corticotropin-releasing hormone CRH receptor hypothalamic–pituitary–adrenal nerve growth factor proopiomelanocortin prolactin substance P T helper Psychological stress is a prevalent aspect of life, usually triggered by a stimulus (stressor), which induces a reaction in the brain (stress perception). Subsequently, additional physiological systems are activated in the body, for example, the immune, endocrine, and nervous systems (stress response) (Cacioppo et al., 1998Cacioppo J.T. Berntson G.G. Malarkey W.B. Kiecolt-Glaser J.K. Sheridan J.F. Poehlmann K.M. et al.Autonomic, neuroendocrine, and immune responses to psychological stress: the reactivity hypothesis.Ann NY Acad Sci. 1998; 840: 664-673Crossref PubMed Scopus (195) Google Scholar). According to Walter Cannon's hypothesis, the stress response is an evolutionarily adaptive psychophysiological survival mechanism that allows the individual to react to an acute stressor — for example, a predator — with either “fight or flight,” and to react to exposure to chronic stress by saving energy (Cannon, 1914Cannon W.B. The emergency function of the adrenal medulla in pain and the major emotions.Am J Physiol. 1914; 33: 356-372Crossref Google Scholar). However, stressors have changed, and the present connotation of stress does not include the survival of the individual based on the putative preparedness to fight or evade predators, or to save energy. Hence, pathophysiological changes associated with the stress response are misrouted and serve as aggravating or triggering factors in the pathogenesis of many diseases, for example, inflammatory, autoimmune, and allergic diseases (Qiu et al., 1999Qiu B.S. Vallance B.A. Blennerhassett P.A. Collins S.M. The role of CD4+ lymphocytes in the susceptibility of mice to stress-induced reactivation of experimental colitis.Nat Med. 1999; 5: 1178-1182Crossref PubMed Scopus (23) Google Scholar; Chandler et al., 2002Chandler N. Jacobson S. Esposito P. Connolly R. Theoharides T.C. Acute stress shortens the time of onset of experimental allergic encephalomyelitis (EAE) in SJL/J mice.Brain Behav Immun. 2002; 16: 757-763Crossref PubMed Scopus (33) Google Scholar; Blois et al., 2005Blois S.M. Tometten M. Kandil J. Hagen E. Klapp B.F. Margni R.A. et al.ICAM-1/LFA-1 cross talk is a proximate mediator capable of disrupting immune integration and tolerance mechanism at the feto-maternal interface in murine pregnancies.J Immunol. 2005; 174: 1820-1829Crossref PubMed Scopus (79) Google Scholar). In a general sense, the term “stress” is widely used, for example in the context of exposure to environmental stressors, as depicted in Figure 1. In this review, we focus predominantly on psychological stress; however, as a relationship between environmental stress and psychological stress is highly suggestive, a discussion of this form of stress has also been included (Figure 1). Activation of neurohormones by psychological stress occurs largely via the hypothalamic–pituitary–adrenal (HPA) axis, with subsequent upregulation of key stress hormones, such as corticotropin-releasing hormone (CRH), ACTH, and glucocorticoids (Cacioppo et al., 1998Cacioppo J.T. Berntson G.G. Malarkey W.B. Kiecolt-Glaser J.K. Sheridan J.F. Poehlmann K.M. et al.Autonomic, neuroendocrine, and immune responses to psychological stress: the reactivity hypothesis.Ann NY Acad Sci. 1998; 840: 664-673Crossref PubMed Scopus (195) Google Scholar; Glaser and Kiecolt-Glaser, 2005Glaser R. Kiecolt-Glaser J.K. Stress-induced immune dysfunction: implications for health.Nat Rev Immunol. 2005; 5: 243-251Crossref PubMed Scopus (1269) Google Scholar). Via these stress-related hormones, accompanied by additional stress response mediators such as neuropeptides or neurotrophins (Webster et al., 2002Webster J.I. Tonelli L. Sternberg E.M. Neuroendocrine regulation of immunity.Annu Rev Immunol. 2002; 20: 125-163Crossref PubMed Scopus (679) Google Scholar), immune responses are profoundly altered (Glaser and Kiecolt-Glaser, 2005Glaser R. Kiecolt-Glaser J.K. Stress-induced immune dysfunction: implications for health.Nat Rev Immunol. 2005; 5: 243-251Crossref PubMed Scopus (1269) Google Scholar). For example, glucocorticoids inhibit the production of IL-12, IFN-γ, and tumor necrosis factor by antigen-presenting cells and T helper 1 (Th1) cells but upregulate the production of IL-4, IL-10, and IL-13 by Th2 cells (Wonnacott and Bonneau, 2002Wonnacott K.M. Bonneau R.H. The effects of stress on memory cytotoxic T lymphocyte-mediated protection against herpes simplex virus infection at mucosal sites.Brain Behav Immun. 2002; 16: 104-117Crossref PubMed Scopus (45) Google Scholar). This may induce the selective suppression of the Th1-mediated cellular immunity and trigger a shift toward Th2-mediated humoral immunity. It has been postulated that this Th2 shift may actually protect the organism from systemic “overshooting” with Th1/proinflammatory cytokines that have tissue-damaging potential (Elenkov et al., 1999Elenkov I.J. Webster E.L. Torpy D.J. Chrousos G.P. Stress, corticotropin-releasing hormone, glucocorticoids, and the immune/inflammatory response: acute and chronic effects.Ann NY Acad Sci. 1999; 876: 1-11Crossref PubMed Scopus (186) Google Scholar). Besides such often-cited immunosuppressive effects of glucocorticoids, relevant examples of proinflammatory actions of CRH — which triggers the release of glucocorticoids — have recently been introduced, for example, in inflammatory arthritis, where both CRH and urocortin have been identified in the joints (McEvoy et al., 2001McEvoy A.N. Bresnihan B. FitzGerald O. Murphy E.P. Corticotropin-releasing hormone signaling in synovial tissue from patients with early inflammatory arthritis is mediated by the type 1a corticotropin-releasing hormone receptor.Arthritis Rheum. 2001; 44: 1761-1767Crossref PubMed Scopus (53) Google Scholar). Elegant experiments with hypophysectomized rats have further proven the effect of additional pituitary hormones — for example, prolactin (PRL) — on the immune system. In these studies, the lack of PRL resulted in abnormalities of the immune system, including increased thymic atrophy and lymphopenia, which could be reversed after grafting of syngeneic pituitary (Chikanza and Panayi, 1991Chikanza I.C. Panayi G.S. Hypothalamic-pituitary mediated modulation of immune function: prolactin as a neuroimmune peptide.Br J Rheumatol. 1991; 30: 203-207Crossref PubMed Scopus (53) Google Scholar). Interestingly, elevated PRL antagonizes apoptosis in thymocytes exposed to glucocorticoids in vivo, which suggests that, under conditions of increased glucocorticoids, such as during stress, elevated PRL functions physiologically to maintain survival and function of T lymphocytes (Krishnan et al., 2003Krishnan N. Thellin O. Buckley D.J. Horseman N.D. Buckley A.R. Prolactin suppresses glucocorticoid-induced thymocyte apoptosis in vivo.Endocrinology. 2003; 144: 2102-2110Crossref PubMed Scopus (69) Google Scholar). Neurohormonal responses to stress also include an activation of the sympathetic nervous system with a subsequent increase of catecholamines, a phenomenon that has received much less attention than the stress-triggered activation of the HPA axis. For half a century it has been known that lymphoid organs are prominently innervated by noradrenergic nerve fibers (Dahlström et al., 1965Dahlström A. Mya-Tu M. Fuxe K. Zetterström B.E. Observations on adrenergic innervation of dog heart.Am J Physiol. 1965; 209: 689-692PubMed Google Scholar), and evidence that has accumulated since then supports the idea that the immune system is regulated via the sympathetic nervous system and catecholamines at the regional, local, and systemic levels (Cacioppo et al., 1998Cacioppo J.T. Berntson G.G. Malarkey W.B. Kiecolt-Glaser J.K. Sheridan J.F. Poehlmann K.M. et al.Autonomic, neuroendocrine, and immune responses to psychological stress: the reactivity hypothesis.Ann NY Acad Sci. 1998; 840: 664-673Crossref PubMed Scopus (195) Google Scholar). For example, lymphocytes express adrenergic receptors and respond to catecholamine stimulation with the development of stress-induced lymphocytosis, and distinct changes in lymphocyte trafficking, circulation, proliferation, and cytokine production (Sanders et al., 1997Sanders V.M. Baker R.A. Ramer-Quinn D.S. Kasprowicz D.J. Fuchs B.A. Street N.E. Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help.J Immunol. 1997; 158: 4200-4210PubMed Google Scholar; Dhabhar, 2000Dhabhar F.S. Acute stress enhances while chronic stress suppresses skin immunity. The role of stress hormones and leukocyte trafficking.Ann NY Acad Sci. 2000; 917: 876-893Crossref PubMed Scopus (203) Google Scholar). Besides the classical stress-related neurohormones — such as the players of the HPA axis (including CRH, ACTH, and cortisol), PRL, and catecholamines — nerve growth factor (NGF) is now recognized as an important parameter in stress responses (Aloe et al., 2002Aloe L. Alleva E. Fiore M. Stress and nerve growth factor: findings in animal models and humans.Pharmacol Biochem Behav. 2002; 73: 159-166Crossref PubMed Scopus (122) Google Scholar). Besides its function as an important trophic factor for peptidergic and sympathetic neurons and their axon sprouting, NGF is increasingly recognized as a potent immunomodulator, promoting cross-talk between neuronal cells, glia, and immune cells and facilitating monocyte/macrophage migration through vascular endothelium (Levi-Montalcini et al., 1996Levi-Montalcini R. Skaper S.D. Dal Toso R. Petrelli L. Leon A. Nerve growth factor: from neurotrophin to neurokine.Trends Neurosci. 1996; 19: 514-520Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar). The skin is exceptionally well suited to serve as a model organ for dissecting the complex neuro-endocrine-immune circuitry invoked during stress responses, for the following reasons: (1) Hardly any other organ is continuously exposed to such a wide range of stressors as the skin, the prototypic environmental interface organ of vertebrate life; and this exposure occurs 24 hours a day during our entire lifetime (Figure 1). (2) A special susceptibility of the skin to acute and/or chronic psychological stress has been described in a wide range of skin diseases, including pruritus, prurigo nodularis, atopic dermatitis, psoriasis, urticaria, acne vulgaris, lichen planus, alopecia areata, and telogen effluvium (Whitlock, 1976Whitlock F.A. Rook A. Psychophysiological aspects of skin disease. In: Major Problems in Dermatology. 8. London, Saunders1976: 1-36Google Scholar; Zouboulis and Böhm, 2004Zouboulis C.C. Böhm M. Neuroendocrine regulation of sebocytes: a pathogenetic link between stress and acne.Exp Dermatol. 2004; 13: 31-35Crossref PubMed Scopus (124) Google 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: 455-457Crossref PubMed Scopus (115) Google Scholar; O'Leary et al., 2004O'Leary C.J. Creamer D. Higgins E. Weinman J. Perceived stress, stress attributions and psychological distress in psoriasis.J Psychosom Res. 2004; 57: 465-471Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). (3) Adaptive skin responses to acute stress, besides classical autonomic-nervous “stress indicators” of the skin such as flushing and sweating, include an enhanced skin immune function with increased intracutaneous extravasation of immunocompetent cells (Dhabhar, 2000Dhabhar F.S. Acute stress enhances while chronic stress suppresses skin immunity. The role of stress hormones and leukocyte trafficking.Ann NY Acad Sci. 2000; 917: 876-893Crossref PubMed Scopus (203) Google Scholar) and increased mast-cell degranulation (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). (4) The skin and its appendages are exquisitely well innervated, and their afferent signals to the central nervous system are relatively overrepresented in the sensory cortex. (5) The skin and its appendages are capable of generating the same mediators that are used during systemic stress responses, and they have established a fully functional peripheral equivalent of the systemic, stress-activated HPA axis (Slominski and Wortsman, 2000Slominski A. Wortsman J. Neuroendocrinology of the skin.Endocr Rev. 2000; 21: 457-487Crossref PubMed Scopus (601) Google Scholar; 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 (377) Google Scholar) (Figure 2). (6) The course of skin disorders (listed in Figure 3) in response to stress and/or various stress-modulatory psychological or pharmacological interventions can easily be followed macroscopically, and skin biopsies for further in-depth histological, immunological, endocrinological, neurobiological, biochemical, and molecular analyses can easily be performed, thus greatly facilitating stress research in both humans and experimental animals. The skin has its own neuroendocrine system, which is tightly linked into systemic neuroendocrine axes, probably in order to coordinate peripheral responses to stress and to maintain cutaneous and global homeostasis (Slominski and Wortsman, 2000Slominski A. Wortsman J. Neuroendocrinology of the skin.Endocr Rev. 2000; 21: 457-487Crossref PubMed Scopus (601) Google Scholar). These activities are organized by the intracutaneous neuroendocrine axes, composed chiefly of a cutaneous equivalent of the HPA axis (Slominski et al., 2002Slominski A. Wortsman J. Kohn L. Ain K.B. Venkataraman G.M. Pisarchik A. et al.Expression of hypothalamic-pituitary-thyroid axis related genes in the human skin.J Invest Dermatol. 2002; 119: 1449-1455Crossref PubMed Scopus (118) Google Scholar; Slominski et al., 2005bSlominski A. Zbytek B. Szczesniewski A. Semak I. Kaminski J. Sweatman T. et al.CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH.Am J Physiol Endocrinol Metab. 2005; 288: E701-E706Crossref PubMed Scopus (164) Google Scholar) (Figures 1 and 2). Recently, a fully functional peripheral equivalent of the HPA axis could be demonstrated in microdissected, organ-cultured human scalp hair follicles, which were capable of synthesizing cortisol and showing fully functional feedback controls (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 (377) Google Scholar). Strikingly, human skin also expresses CRH and, additionally, urocortin mRNA and protein (Slominski et al., 2002Slominski A. Wortsman J. Kohn L. Ain K.B. Venkataraman G.M. Pisarchik A. et al.Expression of hypothalamic-pituitary-thyroid axis related genes in the human skin.J Invest Dermatol. 2002; 119: 1449-1455Crossref PubMed Scopus (118) Google Scholar). Murine skin contains CRH protein but has not been shown to contain CRH mRNA (though it does express both transcripts and protein for the CRH receptor ligand urocortin). Hence, the neural delivery of CRH into the skin must also be considered as a possible means by which CRH protein can be transported into the skin in a highly localized fashion (Roloff et al., 1998Roloff B. Fechner K. Slominski A. Hair cycle-dependent expression of corticotropin-releasing factor (crf) and crf receptors in murine skin.FASEB J. 1998; 12: 287-297PubMed Google Scholar). Most recently, the expression of urocortin II (stresscopin-related peptide) mRNA in both human and mouse skin could be detected, and corresponding receptors for these ligands were also identified in skin cells (Pisarchik and Slominski, 2001Pisarchik A. Slominski A. Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression.FASEB J. 2001; 15: 2754-2756PubMed Google Scholar). CRH-like immunoreactivity is further present in the dorsal horn of the spinal cord and dorsal root ganglia (Skofitsch et al., 1985Skofitsch G. Zamir N. Helke C.J. Savitt J.M. Jacobowitz D.M. Corticotropin-releasing factor-like immunoreactivity in sensory ganglia and capsaicin sensitive neurons of the rat central nervous system: colocalization with other neuropeptides.Peptides. 1985; 6: 307-318Crossref PubMed Scopus (100) Google Scholar), as well as in sympathetic ganglia (Merchenthaler et al., 1983Merchenthaler I. Hynes M.A. Vingh S. Schally A.V. Petrusz P. Immunocytochemical localization of corticotropin-releasing factor (CRF) in the rat spinal cord.Brain Res. 1983; 275: 373-377Crossref PubMed Scopus (105) Google Scholar). Strikingly, acute stress increases the skin content of CRH, which may derive from dorsal root ganglia (Theoharides and Bielory, 2004Theoharides T.C. Bielory L. Mast cells and mast cell mediators as targets of dietary supplements.Ann Allergy Asthma Immunol. 2004; 93: S24-S34Abstract Full Text PDF PubMed Scopus (54) Google Scholar). Mapping of the cutaneous CRH signaling system in humans revealed that the CRH receptor type 1 (CRH-R1) is expressed in all major cellular populations of epidermis, dermis, and subcutis. CRH-R1 appears to be the most prevalent isoform of CRH-R, and the CRH-R2 gene is expressed solely in the dermis and adnexal structures. In mouse skin, the CRH-R2 gene and protein are widely expressed in all cutaneous compartments. The pathophysiological relevance of CRH-R1 may be reflected by the observation that CRH-R1 is involved in stress-induced exacerbation of chronic contact dermatitis in rats (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). Interestingly, affected scalp skin areas from patients with alopecia areata, which may be precipitated by psychological stress, show increased expression of CRH-R2 around hair follicles (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). Furthermore, affected skin areas from patients with contact dermatitis and chronic urticaria have increased expression of CRH-R1, as compared with normal control skin (TC Theoharides, unpublished data). Although the importance of CRH-R in the skin stress response is highly probable, the functional role of CRH-R expression in pathological human skin conditions remains to be identified. Hypothalamic CRH production and secretion represent the most proximal end of the systemic HPA axis. CRH activates CRH-R1 and induces production and release of the proopiomelanocortin (POMC)-derived peptides ACTH, α-melanocyte-stimulating hormone, and β-endorphin in the pituitary gland (Slominski and Wortsman, 2000Slominski A. Wortsman J. Neuroendocrinology of the skin.Endocr Rev. 2000; 21: 457-487Crossref PubMed Scopus (601) Google Scholar). ACTH, in turn, stimulates the production and secretion of cortisol or corticosterone by the adrenal cortex, which counteract the effect of the stressors by suppression of the HPA axis through a negative feedback mechanism (Slominski and Wortsman, 2000Slominski A. Wortsman J. Neuroendocrinology of the skin.Endocr Rev. 2000; 21: 457-487Crossref PubMed Scopus (601) Google Scholar). Mammalian skin expresses POMC and produces the POMC-derived peptides β-endorphin, ACTH, α-melanocyte-stimulating hormone, and β-lipocortin. The first full demonstration of the cutaneous expression of POMC was accomplished in mouse skin (Slominski et al., 1991Slominski A. Paus R. Mazurkiewicz J. Pro-opiomelanocortin expression and potential function of pro-opiomelanocortin products during induced hair growth in mice.Ann NY Acad Sci. 1991; 642: 459-461Crossref PubMed Scopus (11) Google Scholar) and this was followed by insights from human skin (Schauer et al., 1994Schauer E. Trautinger F. Kock A. Schwarz A. Bhardwaj R. Simon M. et al.Proopiomelanocortin-derived peptides are synthesized and released by human keratinocytes.J Clin Invest. 1994; 93: 2258-2262Crossref PubMed Scopus (310) Google Scholar). The presence of β-endorphin, ACTH, α-melanocyte-stimulating hormone, and their modified forms in the skin was confirmed both by reverse-phase (RP)-HPLC separation and by liquid-chromatography mass spectrometry. In light of the existence of a local, neuroendocrine skin axis, it has been proposed that the cutaneous defense against stressors is organized similarly to the classical HPA axis. Effectors of this axis (CRH, urocortin, and POMC peptides) are capable of regulating skin pigmentary, immune, epidermal, dermal, and adnexal systems (see Böhm et al., 2006, this issue). In this context, environmental challenges such as UV light and biological or chemical stress (Figure 1) trigger multiple pathways involving structuralized or simultaneous local production of CRH-related and POMC-derived messages (Slominski et al., 2005aSlominski A. Wortsman J. Tobin D.J. The cutaneous serotoninergic/melatoninergic system: securing a place under the sun.FASEB J. 2005; 19: 176-194Crossref PubMed Scopus (273) Google Scholar), possibly to counteract the local effects of the environmental stress. This complex response would be susceptible to feedback inhibition by cortisol and/or corticosterone, which are produced locally in the skin (Slominski et al., 2005aSlominski A. Wortsman J. Tobin D.J. The cutaneous serotoninergic/melatoninergic system: securing a place under the sun.FASEB J. 2005; 19: 176-194Crossref PubMed Scopus (273) Google Scholar; 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 (377) Google Scholar). The skin expresses the molecular apparatus necessary for the synthesis of adrenal and adrenal-like glucocorticosteroids. Specifically, production of deoxycorticosterone, corticosterone, and cortisol was documented in vitro (Slominski et al., 2005aSlominski A. Wortsman J. Tobin D.J. The cutaneous serotoninergic/melatoninergic system: securing a place under the sun.FASEB J. 2005; 19: 176-194Crossref PubMed Scopus (273) Google Scholar). Hence there is now experimental evidence that CRH triggers a functional cascade structured hierarchically along the same algorithm as in the classical HPA axis: CRH activates CRH-R1, stimulates cAMP accumulation, and increases production of ACTH with enhanced production of cortisol and corticosterone in melanocytes, of corticosterone but not cortisol in fibroblasts (Slominski et al., 2005bSlominski A. Zbytek B. Szczesniewski A. Semak I. Kaminski J. Sweatman T. et al.CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH.Am J Physiol Endocrinol Metab. 2005; 288: E701-E706Crossref PubMed Scopus (164) Google Scholar), and of ACTH and cortisol in human scalp hair follicle epithelium in situ (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 (377) Google Scholar). This intracutaneous equivalent of the systemic HPA axis is complemented by additional neuroendocrine activities of the skin, whose role in cutaneous stress responses remains to be determined. For example, murine skin and hair follicles as well as human scalp hair follicles also express PRL, another key neuroendocrine signal whose level rises sharply during psychological stress responses (Sonino et al., 2004Sonino N. Navarrini C. Ruini C. Fallo F. Boscaro M. Fava G.A. Life events in the pathogenesis of hyperprolactinemia.Eur J Endocrinol. 2004; 151: 61-65Crossref PubMed Scopus (45) Google Scholar). In addition, the skin and its pilosebaceous units display a complete local serotoninergic/melatoninergic system (Slominski et al., 2005bSlominski A. Zbytek B. Szczesniewski A. Semak I. Kaminski J. Sweatman T. et al.CRH stimulation of corticosteroids production in melanocytes is mediated by ACTH.Am J Physiol Endocrinol Metab. 2005; 288: E701-E706Crossref PubMed Scopus (164) Google Scholar), which includes the capacity to synthesize melatonin (Kobayashi et al., 2005Kobayashi H. Kromminga A. Dunlop T.W. Tychsen B. Conrad F. Suzuki N. et al.A role of melatonin in neuroectodermal-mesodermal interactions: the hair follicle synthesizes melatonin and expresses functional melatonin receptors.FASEB J. 2005; 19: 1710-1712PubMed Google Scholar), the most effective neurohormonal scavenger of reactive oxygen species (Fischer and Elsner, 2001Fischer T.W. Elsner P. The antioxidative potential of melatonin in the skin.Curr Probl Dermatol. 2001; 29: 165-174Crossref PubMed Google Scholar). Whether or not recently discovered elements of a pituitary–thyroid axis, which are also expressed in the skin (Slominski et al., 2002Slominski A. Wortsman J. Kohn L. Ain K.B. Venkataraman G.M. Pisarchik A. et al.Expression of hypothalamic-pituitary-thyroid axis related genes in the human skin.J Invest Dermatol. 2002; 119: 1449-1455Crossref PubMed Scopus (118) Google Scholar), and the intracutaneous synthesis of catecholamines also feed into skin responses to psychological stress can currently only be speculated on and constitutes an important open question for future neuroendocrine and neuroimmunological research into cutaneous stress responses. Human mast cells are activated by a plethora of mast-cell secretagogues and other mediators (Figure 3) (Theoharides and Conti, 2004Theoharides T.C. Conti P. Mast cells: the Jekyll and Hyde of tumor growth.Trends Immunol. 2004; 25: 235-241Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). This includes the stress hormones ACTH and CRH, as skin mast cells express five CRH-R1 isoforms as well as CRH-R2α (Pisarchik and Slominski, 2001Pisarchik A. Slominski A. Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression.FASEB J. 2001; 15: 2754-2756PubMed Google Scholar). Strikingly, besides hair follicles, skin mast cells may be among the richest sources of CRH outside the brain (Kempuraj et al., 2001). Thus, skin mast cells not only are hi" @default.
• W1972558580 created "2016-06-24" @default.
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• W1972558580 date "2006-08-01" @default.
• W1972558580 modified "2023-10-11" @default.
• W1972558580 title "Neuroimmunology of Stress: Skin Takes Center Stage" @default.
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