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Skin Corticotropin-Releasing Hormone Receptor Expression in Psoriasis

2007; Elsevier BV; Volume: 127; Issue: 7 Linguagem: Inglês

10.1038/sj.jid.5700757

1523-1747

Michael Tagen, Linsey Stiles, Demetrios Kalogeromitros, Stamatios Gregoriou, Duraisamy Kempuraj, Μichael Μakris, Jill Donelan, Magdalini Vasiadi, Nikolaos G. Staurianeas, Theoharis C. Theoharides,

Allergic Rhinitis and Sensitization

corticotropin-releasing hormone hypothalamic–pituitary–adrenal CRH receptor-1 psoriasis area and severity index TO THE EDITOR Psoriasis is characterized by keratinocyte proliferation, inflammation, and mast cell activation (Schon and Boehncke, 2005Schon M.P. Boehncke W.H. Psoriasis.N Engl J Med. 2005; 352: 1899-1912Crossref PubMed Scopus (962) Google Scholar). It is also triggered or exacerbated by acute stress (Katsarou-Katsari et al., 1999Katsarou-Katsari A. Filippou A. Theoharides T.C. Effect of stress and other psychological factors on the pathophysiology and treatment of dermatoses.Int J Immunopathol Pharmacol. 1999; 12: 7-11PubMed Google Scholar; Saraceno et al., 2006Saraceno R. Kleyn C.E. Terenghi G. Griffiths C.E. The role of neuropeptides in psoriasis.Br J Dermatol. 2006; 155: 876-882Crossref PubMed Scopus (100) Google Scholar); however, this mechanism remains poorly understood. Stress typically results in release of corticotropin-releasing hormone (CRH) from the hypothalamus and regulates the hypothalamic–pituitary–adrenal (HPA) axis (Chrousos, 1995Chrousos G.P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.N Engl J Med. 1995; 332: 1351-1362Crossref PubMed Scopus (2116) Google Scholar) through activation of CRH receptor-1 (CRH-R1), leading to immunosuppression. CRH is also found peripherally (Chrousos, 1995Chrousos G.P. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation.N Engl J Med. 1995; 332: 1351-1362Crossref PubMed Scopus (2116) Google Scholar) and has pro-inflammatory effects through mast cell activation (Theoharides et al., 1998Theoharides T.C. Singh L.K. Boucher W. Pang X. Letourneau R. Webster E. et al.Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its pro-inflammatory effects.Endocrinology. 1998; 139: 403-413Crossref PubMed Google Scholar). CRH and CRH-R gene expression has been documented in rodent and human skin (Slominski et al., 2001Slominski A. Wortsman J. Pisarchik A. Zbytek B. Linton E.A. Mazurkiewicz J.E. et al.Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors.FASEB J. 2001; 15: 1678-1693Crossref PubMed Scopus (229) Google Scholar). In fact, it has been proposed that skin has the equivalent of the HPA axis (Slominski et al., 2000Slominski 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: 979-1020Crossref PubMed Scopus (599) Google Scholar). In mice, CRH is released from nerve endings (Slominski et al., 2001Slominski A. Wortsman J. Pisarchik A. Zbytek B. Linton E.A. Mazurkiewicz J.E. et al.Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors.FASEB J. 2001; 15: 1678-1693Crossref PubMed Scopus (229) Google Scholar), whereas in humans it is synthesized by skin cells (Slominski et al., 1998Slominski A. Ermak G. Mazurkiewicz J.E. Baker J. Wortsman J. Characterization of corticotropin-releasing hormone (CRH) in human skin.J Clin Endocrinol Metab. 1998; 83: 1020-1024Crossref PubMed Scopus (100) Google Scholar), immune cells (Karalis et al., 1997Karalis K. Louis J.M. Bae D. Hilderbrand H. Majzoub J.A. CRH and the immune system.J Neuroimmunol. 1997; 72: 131-136Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar), and human mast cells (Kempuraj et al., 2004Kempuraj D. Papadopoulou N.G. Lytinas M. Huang M. Kandere-Grzybowska K. Madhappan B. et al.Corticotropin-releasing hormone and its structurally related urocortin are synthesized and secreted by human mast cells.Endocrinology. 2004; 145: 43-48Crossref PubMed Scopus (154) Google Scholar). To study the effect of stress and the role of CRH in psoriasis, we investigated, by quantitative PCR, CRH-R expression in affected and unaffected skin of psoriasis patients (n=13) and skin from normal controls (n=4), as well as serum CRH levels from psoriasis patients (n=8) and controls (n=4). The characteristics of the subjects (Table S1) were as follows: male mean age 47.4±7.0 years (n=7); female mean age 28.0±5.2 years (n=6); normal subjects (one male, three female subjects, mean age 40±15.2 years). All skin biopsies requiring two stitches were collected for diagnostic purposes (Table S1). The Medical Ethics Committee of Attikon Hospital HIRB approved this protocol. All participants gave their written informed consent according to the Declaration of Helsinki Principles. Patients had moderate chronic plaque psoriasis with psoriasis area and severity index (PASI) scores 5–16 and had not received any therapy for psoriasis (topical or systemic) for the past month. The PASI score for males was 11.3±13.5 and for females was 11.5±3.7. Download .pdf (.08 MB) Help with pdf files Supplementary Table S1 Expression of CRH-R1 mRNA was lowest in affected samples from psoriasis patients (0.27±0.23, n=13, P<0.05), compared with control patients (Figure 1a). CRH-R1 expression in unaffected skin from psoriasis patients (0.53±0.38) was not statistically different from that of affected samples or controls (Figure 1a). There was no statistically significant difference in CRH-R2 mRNA expression among the control samples, those obtained from affected (0.86±0.51) and from unaffected (0.97±0.65) psoriatic skin (Figure 1a). The serum CRH level (11.52± 6.09 pg/ml) was higher (n=8, P<0.05) in psoriasis patients than controls (5.42±1.2 pg/ml, n=8). There was no apparent correlation between the PASI scores and either CRH-R1 expression or serum CRH levels. This study provides early evidence that affected psoriatic skin has decreased gene expression of CRH-R1 mRNA than normal controls. One possible explanation is that overstimulation by increased levels of local or systemic (serum) CRH in psoriasis patients, possibly in response to chronic stress, may lead to CRH-R1 downregulation. In fact, CRH protein expression was recently reported to be increased in the affected skin of three patients with active psoriasis than in one control; however, this effect was not quantitated (O'Kane et al., 2006O'Kane M. Murphy E.P. Kirby B. The role of corticotropin-releasing hormone in immune-mediated cutaneous inflammatory disease.Exp Dermatol. 2006; 15: 143-153Crossref PubMed Scopus (75) Google Scholar). As non-affected psoriatic skin apparently did not overexpress CRH-R, as shown by our quantitative real-time–PCR data, there was apparently no mechanism in place to lead to downregulation. Increased CRH-R expression in psoriatic skin was also mentioned as "unpublished observations" (O'Kane et al., 2006O'Kane M. Murphy E.P. Kirby B. The role of corticotropin-releasing hormone in immune-mediated cutaneous inflammatory disease.Exp Dermatol. 2006; 15: 143-153Crossref PubMed Scopus (75) Google Scholar) and it is, therefore, difficult to evaluate it. The reduction in CRH-R1 mRNA expression in affected skin of patients with psoriasis we observed could be due to the intense inflammation seen in plaques without any association with serum CRH levels; however, this possibility is not supported by the literature. In fact, we showed that the inflammation-related molecules IL-1, IL-4, and lipopolysaccharide had no effect on CRH-R1 expression, but increased CRH-R2 expression in human mast cells (Papadopoulou et al., 2005Papadopoulou N.G. Oleson L. Kempuraj D. Donelan J. Cetrulo C.L. Theoharides T.C. Regulation of corticotropin-releasing hormone receptor-2 expression in human cord blood-derived cultured mast cells.J Mol Endocrinol. 2005; 35: R1-R8Crossref PubMed Scopus (30) Google Scholar). CRH-R1 is expressed in keratinocytes (Slominski and Wortsman, 2000Slominski A. Wortsman J. Neuroendocrinology of the skin.Endocr Rev. 2000; 21: 457-487Crossref PubMed Scopus (601) Google Scholar) and in a subpopulation of skin mast cells (Donelan et al., 2006Donelan J. Marchand J. Kempuraj D. Papadopoulou N. Theoharides T.C. Perifollicular and perivascular mouse skin mast cells express corticotropin-releasing hormone receptor.J Inv Dermatol. 2006; 126: 929-932Crossref PubMed Scopus (15) Google Scholar). Normal cultured human mast cells also express mRNA and protein for CRH-R1 and CRH-R2 (Cao et al., 2005Cao J. Papadopoulou N. Kempuraj D. Boucher W.S. Sugimoto K. Cetrulo C.L. et al.Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor.J Immunol. 2005; 174: 7665-7675Crossref PubMed Scopus (263) Google Scholar). Human skin, squamous cell carcinoma, and melanoma cells also express CRH and CRH-R1 (Slominski et al., 1998Slominski A. Ermak G. Mazurkiewicz J.E. Baker J. Wortsman J. Characterization of corticotropin-releasing hormone (CRH) in human skin.J Clin Endocrinol Metab. 1998; 83: 1020-1024Crossref PubMed Scopus (100) Google Scholar, Slominski et al., 2001Slominski A. Wortsman J. Pisarchik A. Zbytek B. Linton E.A. Mazurkiewicz J.E. et al.Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors.FASEB J. 2001; 15: 1678-1693Crossref PubMed Scopus (229) Google Scholar). The lack of any significant difference between affected and unaffected or control skin may either indicate (a) that unaffected skin represents an early or intermediate stage, (b) that these areas have different number of cells expressing CRHR, or (c) the variability is too large, given the small number of patients. Psoriasis is the most common chronic inflammatory skin disorder (Schon and Boehncke, 2005Schon M.P. Boehncke W.H. Psoriasis.N Engl J Med. 2005; 352: 1899-1912Crossref PubMed Scopus (962) Google Scholar). It is worsened by stress (Katsarou-Katsari et al., 1999Katsarou-Katsari A. Filippou A. Theoharides T.C. Effect of stress and other psychological factors on the pathophysiology and treatment of dermatoses.Int J Immunopathol Pharmacol. 1999; 12: 7-11PubMed Google Scholar) and is characterized by aberrant HPA function (Richards et al., 2005Richards H.L. Ray D.W. Kirby B. Mason D. Plant D. Main C.J. et al.Response of the hypothalamic-pituitary-adrenal axis to psychological stress in patients with psoriasis.Br J Dermatol. 2005; 153: 1114-1120Crossref PubMed Scopus (86) Google Scholar); moreover, neuropeptides appear to induce skin neurogenic inflammation (Saraceno et al., 2006Saraceno R. Kleyn C.E. Terenghi G. Griffiths C.E. The role of neuropeptides in psoriasis.Br J Dermatol. 2006; 155: 876-882Crossref PubMed Scopus (100) Google Scholar). The skin may have its own equivalent of the HPA axis (Slominski et al., 2000Slominski 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: 979-1020Crossref PubMed Scopus (599) Google Scholar; Slominski and Wortsman, 2000Slominski A. Wortsman J. Neuroendocrinology of the skin.Endocr Rev. 2000; 21: 457-487Crossref PubMed Scopus (601) Google Scholar) and the role of CRH in cutaneous inflammatory diseases was reviewed recently (O'Kane et al., 2006O'Kane M. Murphy E.P. Kirby B. The role of corticotropin-releasing hormone in immune-mediated cutaneous inflammatory disease.Exp Dermatol. 2006; 15: 143-153Crossref PubMed Scopus (75) Google Scholar). Chronic stress and CRH typically attenuate immune processes, whereas acute stress enhances antigen-specific, cell-mediated immunity (Dhabhar and McEwen, 1999Dhabhar F.S. McEwen B.S. Enhancing versus suppressive effects of stress hormones on skin immune function.Proc Natl Acad Sci USA. 1999; 96: 1059-1064Crossref PubMed Scopus (520) Google Scholar). Stress also exacerbates 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). Acute stress induces local release of CRH in the skin (Lytinas et al., 2003Lytinas M. Kempuraj D. Huang M. Boucher W. Esposito P. Theoharides T.C. Acute stress results in skin corticotropin-releasing hormone secretion, mast cell activation and vascular permeability, an effect mimicked by intradermal corticotropin-releasing hormone and inhibited by histamine-1 receptor antagonists.Int Arch Allergy Immunol. 2003; 130: 224-231Crossref PubMed Scopus (68) Google Scholar) and increases skin vascular permeability (Singh et al., 1999Singh L.K. Pang X. Alexacos N. Letourneau R. Theoharides T.C. Acute immobilization stress triggers skin mast cell degranulation via corticotropin releasing hormone, neurotensin and substance P: a link to neurogenic skin disorders.Brain Behav Immunity. 1999; 13: 225-239Crossref PubMed Scopus (303) Google Scholar), an effect mimicked by intradermal CRH and absent in mast cell-deficient mice (Theoharides et al., 1998Theoharides T.C. Singh L.K. Boucher W. Pang X. Letourneau R. Webster E. et al.Corticotropin-releasing hormone induces skin mast cell degranulation and increased vascular permeability, a possible explanation for its pro-inflammatory effects.Endocrinology. 1998; 139: 403-413Crossref PubMed Google Scholar). CRH also increased vascular permeability in human skin, an effect dependent on CRH-R1 and mast cells (Crompton et al., 2003Crompton R. Clifton V.L. Bisits A.T. Read M.A. Smith R. Wright I.M. Corticotropin-releasing hormone causes vasodilation in human skin via mast cell-dependent pathways.J Clin Endocrinol Metab. 2003; 88: 5427-5432Crossref PubMed Scopus (77) Google Scholar). The level of stress in these patients was not quantitated with any validated instrument and it is, therefore, premature to try to make any correlations between our findings and any level of stress in these patients. Mast cells are involved not only in allergic reactions, but also in innate immunity (Galli et al., 2005Galli S.J. Nakae S. Tsai M. Mast cells in the development of adaptive immune responses.Nat Immunol. 2005; 6: 135-142Crossref PubMed Scopus (986) Google Scholar) and inflammation (Theoharides and Cochrane, 2004Theoharides T.C. Cochrane D.E. Critical role of mast cells in inflammatory diseases and the effect of acute stress.J Neuroimmunol. 2004; 146: 1-12Abstract Full Text Full Text PDF PubMed Scopus (354) Google Scholar). Mast cells are juxtaposed to nerve endings during hair follicle formation (Roloff et al., 1998Roloff B. Fechner K. Slominski A. Furkert J. Botchkarev V.A. Bulfone-Paus S. et al.Hair cycle-dependent expression of corticotropin-releasing factor (CRF) and CRF receptors in murine skin.FASEB J. 1998; 12: 287-297PubMed Google Scholar) and are located close to CRH-positive nerve endings (Rozniecki et al., 1999Rozniecki J.J. Dimitriadou V. Lambracht-Hall M. Pang X. Theoharides T.C. Morphological and functional demonstration of rat dura mast cell-neuron interactions in vitro and in vivo.Brain Res. 1999; 849: 1-15Crossref PubMed Scopus (166) Google Scholar), suggesting that they are involved in a "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 (245) Google Scholar), as targets of CRH and related peptides (Theoharides et al., 2004Theoharides T.C. Donelan J.M. Papadopoulou N. Cao J. Kempuraj D. Conti P. Mast cells as targets of corticotropin-releasing factor and related peptides.Trends Pharmacol Sci. 2004; 25: 563-568Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar). The present findings suggest that CRH and CRH-R1 may participate in the pathogenesis of psoriasis, especially when worsened by stress. The authors state no conflict of interest. Use of CRH-R antagonists in stress-induced dermatoses is covered by US Patents no. 6020305 and 6689748 (TCT). Aspects of this work were supported by US NIH Grant no. AR47652 (TCT). We thank Dr Michael Court (Tufts University) for providing the 18S primers. We also thank Miss Jessica Christian for her word processing skills. Methods. Table S1. Characteristics of subjects providing the skin samples.