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Increased nerve growth factor and its receptors in atopic dermatitis: an immunohistochemical study

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Abstract

Evidence suggests that neurotrophins may regulate certain immune functions and inflammation. In the present study, the localization and distribution of nerve growth factor (NGF) and its receptors were explored using immunohistochemical methods, with the aim of detecting the cause of the neurohyperplasia in early lesions of atopic dermatitis (AD). In AD involved skin, strong NGF-immunoreactive (IR) cells were observed in the epidermis. In some cases, a huge number of infiltrating cells with stronger NGF immunoreactivity was seen mainly in the dermal papillae. Some trkA immunoreactivity was observed in the outer membrane of cells in the basal and spinal layers of the epidermis. In the papillary dermis, a larger number of cells demonstrated strong trkA immunoreactivity. The p75 NGFr-IR nerve fibre profiles were increased (900 per mm2; p<0.001) compared to normal [the involved skin also differed from the uninvolved skin (p<0.05)] in the dermal papillae. These nerve fibres were larger, coarser and branched, some of them terminated at p75 NGFr-IR basal cells, and also revealed a stronger fluorescence staining than the controls or the uninvolved skin. In normal healthy volunteers and AD uninvolved skin, the NGF immunoreactivity was weak in the basal layer of epidermis. Only a few trkA positive cells were seen in the basal layer of the epidermis and upper dermis. The IR epidermal basal cells revealed a striking patchy arrangement with strong p75 NGFr immunostaining in the peripheral part of the cells, and short and thick NGFr-IR nerve fibre profiles appeared as smooth endings scattered in the dermis including the cutaneous accessory organs. Using NGF and p75 NGFr double staining, both immunoreactivities showed a weak staining in the epidermis and dermis in normal and uninvolved skin. In the involved dermis of AD, the intensity of p75 NGFr-IR nerves was stronger in areas where there were also increased numbers of NGF-IR cells. These findings indicate that NGF and its receptors may contribute to the neurohyperplasia of AD.

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Abbreviations

AD:

Atopic dermatitis

NGF:

Nerve growth factor

NGFr:

Nerve growth factor receptor

IR:

Immunoreactive

RRX:

Rhodamine red-X

FITC:

Fluorescein-isothiocyanate

References

  1. Angeletti PU, Levi-Montalcini R, Calissano P (1968) The nerve growth factor (NGF): chemical properties and metabolic effects. Adv Enzymol Relat Areas Mol Biol 31:51–75

    Article  PubMed  CAS  Google Scholar 

  2. Barouch R, Appel E, Kazimirsky G, Braun A, Renz H, Brodie C (2000) Differential regulation of neurotrophin expression by mitogens and neurotransmitters in mouse lymphocytes. J Neuroimmunol 103:112–121

    Article  PubMed  CAS  Google Scholar 

  3. Bothwell M (1991) Keeping track of neurotrophin receptors. Cell 65:915–918

    Article  PubMed  CAS  Google Scholar 

  4. Brodeur GM, Nakagawara A, Yamashiro DJ, Ikegaki N, Liu XG, Azar CG, Lee CP, Evans AE (1997) Expression of TrkA, TrkB and TrkC in human neuroblastomas. J Neurooncol 31:49–55

    Article  PubMed  CAS  Google Scholar 

  5. Chan SC, Hanifin JM (1993) Differential inhibitor effects on cyclic adenosine monophosphate-phosphodiesterase isoforms in atopic and normal leukocytes. J Lab Clin Med 121:44–51

    PubMed  CAS  Google Scholar 

  6. Darsow U, Ring J (2001) Neuroimmune interactions in the skin. Curr Opin Allergy Clin Immunol 1:435–439

    PubMed  CAS  Google Scholar 

  7. Davis BM, Fundin BT, Albers KM, Goodness TP, Cronk KM, Rice FL (1997) Overexpression of nerve growth factor in skin causes preferential increases among innervation to specific sensory targets. J Comp Neurol 387:489–506

    Article  PubMed  CAS  Google Scholar 

  8. Di Marco E, Marchisio PC, Bondanza S, Franzi AT, Cancedda R, De Luca M (1991) Growth-regulated synthesis and secretion of biologically active nerve growth factor by human keratinocytes. J Biol Chem 266:21718–21722

    PubMed  CAS  Google Scholar 

  9. Fantini F, Johansson O (1992) Expression of growth-associated protein 43 and nerve growth factor receptor in human skin: a comparative immunohistochemical investigation. J Invest Dermatol 99:734–742

    Article  PubMed  CAS  Google Scholar 

  10. Garcia-Suarez O, Hannestad J, Esteban I, Sainz R, Naves FJ, Vega JA (1998) Expression of the TrkB neurotrophin receptor by thymic macrophages. Immunology 94:235–241

    Article  PubMed  CAS  Google Scholar 

  11. Goodness TP, Albers KM, Davis FE, Davis BM (1997) Overexpression of nerve growth factor in skin increases sensory neuron size and modulates Trk receptor expression. Eur J Neurosci 9:1574–1585

    Article  PubMed  CAS  Google Scholar 

  12. Hamada A, Watanabe N, Ohtomo H, Matsuda H (1996) Nerve growth factor enhances survival and cytotoxic activity of human eosinophils. Br J Haematol 93:299–302

    Article  PubMed  CAS  Google Scholar 

  13. Hempstead BL, Martin-Zanca D, Kaplan DR, Parada LF, Chao MV (1991) High-affinity NGF binding requires coexpression of the trk proto-oncogene and the low-affinity NGF receptor. Nature 350:678–683

    Article  PubMed  CAS  Google Scholar 

  14. Johnson D, Lanahan A, Buck CR, Sehgal A, Morgan C, Mercer E, Bothwell M, Chao M (1986) Expression and structure of the human NGF receptor. Cell 47:545–554

    Article  PubMed  CAS  Google Scholar 

  15. Kaplan DR, Hempstead BL, Martin-Zanca D, Chao MV, Parada LF (1991) The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252:554–558

    Article  PubMed  CAS  Google Scholar 

  16. Korsching S, Thoenen H (1983) Nerve growth factor in sympathetic ganglia and corresponding target organs of the rat: correlation with density of sympathetic innervation. Proc Natl Acad Sci USA 80:3513–3516

    Article  PubMed  CAS  Google Scholar 

  17. Levi-Montalcini R, Skaper SD, Dal Toso R, Petrelli L, Leon A (1996) Nerve growth factor: from neurotrophin to neurokine. Trends Neurosci 19:514–520

    Article  PubMed  CAS  Google Scholar 

  18. Liang Y, Johansson O (1998) Light and electron microscopic demonstration of the p75 nerve growth factor receptor in normal human cutaneous nerve fibers: new vistas. J Invest Dermatol 111:114–118

    Article  PubMed  CAS  Google Scholar 

  19. Liang Y, Marcusson JA, Johansson O (1999) Light and electron microscopic immunohistochemical observations of p75 nerve growth factor receptor-immunoreactive dermal nerves in prurigo nodularis. Arch Dermatol Res 291:14–21

    Article  PubMed  CAS  Google Scholar 

  20. Melamed I, Kelleher CA, Franklin RA, Brodie C, Hempstead B, Kaplan D, Gelfand EW (1996) Nerve growth factor signal transduction in human B lymphocytes is mediated by gp140trk. Eur J Immunol 26:1985–1992

    Article  PubMed  CAS  Google Scholar 

  21. Mizuma H, Takagi K, Miyake K, Takagi N, Ishida K, Takeo S, Nitta A, Nomoto H, Furukawa Y, Furukawa S (1999) Microsphere embolism-induced elevation of nerve growth factor level and appearance of nerve growth factor immunoreactivity in activated T-lymphocytes in the rat brain. J Neurosci Res 55:749–761

    Article  PubMed  CAS  Google Scholar 

  22. Pierce JH, Arnstein P, DiMarco E, Artrip J, Kraus MH, Lonardo F, Di Fiore PP, Aaronson SA (1991) Oncogenic potential of erbB-2 in human mammary epithelial cells. Oncogene 6:1189–1194

    PubMed  CAS  Google Scholar 

  23. Pincelli C, Sevignani C, Manfredini R, Grande A, Fantini F, Bracci-Laudiero L, Aloe L, Ferrari S, Cossarizza A, Giannetti A (1994) Expression and function of nerve growth factor and nerve growth factor receptor on cultured keratinocytes. J Invest Dermatol 103:13–18

    Article  PubMed  CAS  Google Scholar 

  24. Pugin J, Heumann ID, Tomasz A, Kravchenko VV, Akamatsu Y, Nishijima M, Glauser MP, Tobias PS, Ulevitch RJ (1994) CD14 is a pattern recognition receptor. Immunity 1:509–516

    Article  PubMed  CAS  Google Scholar 

  25. Shyne-Athwal S, Chakraborty G, Gage E, Ingoglia NA (1988) Comparison of posttranslational protein modification by amino acid addition after crush injury to sciatic and optic nerves of rats. Exp Neurol 99:281–295

    Article  PubMed  CAS  Google Scholar 

  26. Solomon A, Aloe L, Pe’er J, Frucht-Pery J, Bonini S, Levi-Schaffer F (1998) Nerve growth factor is preformed in and activates human peripheral blood eosinophils. J Allergy Clin Immunol 102:454–460

    Article  PubMed  CAS  Google Scholar 

  27. Stepien H, Lyson K, Stanisz AM, Pawlikowski M (1991) The effect of nerve growth factor on DNA synthesis, cyclic AMP and cyclic GMP accumulation by mouse spleen lymphocytes. Int J Immunopharmacol 13:51–56

    Article  PubMed  CAS  Google Scholar 

  28. Toyoda M, Nakamura M, Makino T, Hino T, Kagoura M, Morohashi M (2002) Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis. Br J Dermatol 147:71–79

    Article  PubMed  CAS  Google Scholar 

  29. Tron VA, Coughlin MD, Jang DE, Stanisz J, Sauder DN (1990) Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212). J Clin Invest 85:1085–1089

    Article  PubMed  CAS  Google Scholar 

  30. Vega JA, Del Valle ME, Haro JJ, Calzada B, Suarez-Garnacho S, Malinovsky L (1993) Nerve growth factor receptor immunoreactivity in Meissner and Pacinian corpuscles of the human digital skin. Anat Rec 236:730–736

    Article  PubMed  CAS  Google Scholar 

  31. Vega JA, Vazquez E, Naves FJ, Del Valle ME, Calzada B, Represa JJ (1994) Immunohistochemical localization of the high-affinity NGF receptor (gp140-trkA) in the adult human dorsal root and sympathetic ganglia and in the nerves and sensory corpuscles supplying digital skin. Anat Rec 240:579–588

    Article  PubMed  CAS  Google Scholar 

  32. Wilkinson DI, Theeuwes MJ, Farber EM (1994) Nerve growth factor increases the mitogenicity of certain growth factors for cultured human keratinocytes: a comparison with epidermal growth factor. Exp Dermatol 3:239–245

    Article  PubMed  CAS  Google Scholar 

  33. Yaar M, Grossman K, Eller M, Gilchrest BA (1991) Evidence for nerve growth factor-mediated paracrine effects in human epidermis. J Cell Biol 115:821–828

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Cancer and Allergy Foundation (Cancer- och Allergifonden). We thank Professor Tomas Hökfelt of the Department of Neuroscience, Karolinska Institute, for general support. We also thank Ms Marianne Ekman for her excellent technical assistance, and Ms Margareta Krook-Brandt of the Department of Learning, Informatics, Management and Ethics/The Medical Statistics Service Group, Karolinska Institute, for her statistical evaluation.

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Authors and Affiliations

  1. Experimental Dermatology Unit, Department of Neuroscience, Karolinska Institute, 171 77, Stockholm, Sweden

    Ying-Chun Dou & Olle Johansson

  2. Department of Dermatology, Karolinska University Hospital, 141 86, Stockholm, Sweden

    Lena Hagströmer & Lennart Emtestam

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  1. Ying-Chun Dou
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  2. Lena Hagströmer
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  4. Olle Johansson
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Correspondence to Olle Johansson.

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Dou, YC., Hagströmer, L., Emtestam, L. et al. Increased nerve growth factor and its receptors in atopic dermatitis: an immunohistochemical study. Arch Dermatol Res 298, 31–37 (2006). https://doi.org/10.1007/s00403-006-0657-1

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  • DOI: https://doi.org/10.1007/s00403-006-0657-1

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