Abstract
Chronic exposure to ultraviolet radiation (UVR) plays a significant role in aging and carcinogenesis of the skin. Sensory nerve fibers densely innervate all layers of the skin and get in close anatomical as well as functional contact with cellular components of the epidermis and dermis. In this review, we address the impact of acute and chronic UVR exposure on the cutaneous sensory nervous system and its mediators. We suggest that skin cell-derived nerve growth factor (NGF) and skin nerve-derived neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) may play a central role in intrinsic aging as well as extrinsic (photo-) aging of the skin. In addition, we discuss the possible role of these mediators in photocarcinogenesis.
Similar content being viewed by others
References
J. Garssen, M. Norval, A. el-Ghorr, N. K. Gibbs, C. D. Jones, D. Cerimele, C. de Simone, S. Caffieri, F. Dall℉Acqua, F. R. de Gruijl, Y Sontag, H van Loveren, Estimation of the effect of increasing UVB exposure on the human immune system and related resistance to infectious diseases and tumours, J. Photochem. Photobiol., B, 1998, 42, 167–179.
I. M. Hadshiew, M. S. Eller, B. A. Gilchrest, Skin aging and photoaging: The role of DNA damage and repair, Am. J. Contact. Dermatitis, 2000, 11, 19–25.
M. Yaar, M. S. Eller, B. A. Gilchrest, Fifty years of skin aging, J. Invest. Dermatol. Symp. Proc., 2002, 7, 51–58.
P. Holzer, Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides, Neuroscience, 1988, 24, 739–768.
F. J. Legat, C. A. Armstrong, T. Scholzen, J. E. Olerud, N. W. Bunnett, T. A. Luger and J. C. Ansel, Neurobiology of the skin, in Fitzpatrick’s Dermatology in General Medicine, ed. I. M. Freedberg, A. Z. Eisen, K. Wolff, K. F. Austen, L. A. Goldsmith and S. I. Katz, McGraw Hill Companies Inc., New York, 2003, pp. 230–235.
P. Langerhans, Uber die Nerven der menschlichen Haut, Virchow℉s Arch., 1868, 44, 325–337.
G. Lauria, Innervation of the human epidermis. A historical review, Ital. J. Neurol. Sci., 1999, 20, 63–70.
L. Wang, M. Hilliges, T. Jernberg, D. Wieberg-Edstrom, O. Johansson, Protein gene product 9.5-immunoreactive nerve fibers and cell in human skin, Cell Tissue Res., 1990, 261, 25–33.
J. Szolcsanyi, Selective responsiveness of polymodal nociceptors of the rabbit ear to capsaicin, bradykinin and ultra-violet irradiation, J. Physiol., 1987, 388, 9–23.
V. Chapman, A. H. Dickenson, Enhanced responses of rat dorsal horn neurons after UV irradiation of the hindpaw; roles of the NMDA receptor, Neurosci. Lett., 1994, 176, 41–44.
F. Gillardon, I. Moll, S. Michel, J. Benrath, E. Weihe, M. Zimmermann, Calcitonin gene-related peptide and nitric oxide are involved in ultraviolet radiation-induced immunosuppression, Eur. J. Pharmacol., 1995, 293, 395–400.
J. Donnerer, R. Schuligoi, C. Stein, Increased content and transport of substance P and calcitonin gene-related peptide in sensory nerves innervating inflamed tissue: evidence for a regulatory function of nerve growth factor in vivo, Neuroscience, 1992, 49, 693–698.
M. Seike, M. Ikeda, A. Morimoto, M. Matsumoto, H. Kodama, Increased synthesis of calcitonin gene-related peptide stimulates keratinocyte proliferation in murine UVB-irradiated skin, J. Dermatol. Sci., 2002, 28, 135–143.
J. Benrath, C. Eschenfelder, M. Zimmerman, F. Gillardon, Calcitonin gene-related peptide, substance P and nitric oxide are involved in cutaneous inflammation following ultraviolet irradiation, Eur. J. Pharmacol., 1995, 293, 87–96.
H. Niizeki, P. Alard, J. W. Streilein, Calcitonin gene-related peptide is necessary for ultraviolet B-impaired induction of contact hypersensitivity, J. Immunol., 1997, 159, 5183–5186.
J. Garssen, T. L. Buckley, H. van Loveren, A role for neuropeptides in UVB-induced systemic immunosuppression, Photochem. Photobiol., 1998, 68, 205–210.
P. H. Hart, S. L. Townley, M. A. Grimbaldeston, Z. Khalil, J. J. Finlay-Jones, Mast cells, neuropeptides, histamine, and prostaglandins in UV-induced systemic immunosuppression, Methods, 2002, 28, 79–89.
S. L. Townley, M. A. Grimbaldeston, I. Ferguson, R. A. Rush, S. H. Zhang, X. F. Zhou, J. M. Conner, J. J. Finlay-Jones, P. H. Hart, Nerve growth factor, neuropeptides, and mast cells in ultraviolet-B-induced systemic suppression of contact hypersensitivity responses in mice, J. Invest. Dermatol., 2002, 118, 396–401.
Z. Khalil, S. L. Townley, M. A. Grimbaldeston, J. J. Finlay-Jones, P. H. Hart, cis-Urocanic acid stimulates neuropeptide release from peripheral sensory nerves, J. Invest. Dermatol., 2001, 117, 886–891.
A. Jaksic, J. J. Finlay-Jones, C. J. Watson, L. K. Spencer, I. Santucci, P. H. Hart, cis-Urocanic acid synergizes with histamine for increased PGE2 production by human keratinocytes: link to indomethacin-inhibitable UVB-induced immunosuppression, Photochem. Photobiol., 1995, 61, 303–309.
O. Johansson, L. Wang, M. Hilliges, Y. Liang, Intraepidermal nerves in human skin: PGP 9.5 immunohistochemistry with special reference to the nerve density in skin from different body regions, J. Peripher. Nerv. Syst., 1999, 4, 43–52.
Y. C. Chang, W. M. Lin, S. T. Hsieh, Effects of aging on the human skin innervation, Neuroreport, 2004, 15, 149–153.
S. T. Hsieh, S. Choi, W. M. Lin, Y. C. Chang, J. C. Mcarthur, J. W. Griffin, Epidermal denervation and its effects on keratinocytes and Langerhans cells, J. Neurocytol., 1996, 25, 513–524.
R. M. Lindsay, A. J. Harmar, Nerve growth factor regulates expression of neuropeptide genes in adult sensory neurons, Nature, 1989, 337, 362–364.
C. Pincelli, C. Sevignani, R. Manfredini, A. Grande, F. Fantini, L. Bracci-Laudiero, L. Aloe, S. Ferrari, A. Cossarizza, A. Giannetti, Expression and function of nerve growth factor and nerve growth factor receptor on cultured keratinocytes, J. Invest. Dermatol., 1994, 103, 13–18.
C. Pincelli, A. Marconi, Autocrine nerve growth factor in human keratinocytes, J. Dermatol. Sci., 2000, 22, 71–79.
C. Pincelli, A. R. Haake, L. Benassi, E. Grassilli, C. Magnoni, D. Ottani, R. Polakowska, C. Franceschi, A. Giannetti, Autocrine nerve growth factor protects human keratinocytes from apoptosis through its high affinity receptor (TRK): a role for BCL-2, J. Invest. Dermatol., 1997, 109, 757–764.
C. Pincelli, Nerve growth factor and keratinocytes: a role in psoriasis, Eur. J. Dermatol., 2000, 10, 85–90.
L. Larkfors, T. Ebendal, S. R. Whittemore, H. Persson, B. Hoffer, L. Olson, Decreased level of nerve growth factor (NGF) and its messenger RNA in the aged rat brain, Brain Res., 1987, 427, 55–60.
M. Hara, M. Toyoda, M. Yaar, J. Bhawan, E. M. Avila, I. R. Penner, B. A. Gilchrest, Innervation of melanocytes in human skin, J. Exp. Med., 1996, 184, 1385–1395.
M. Toyoda, Y. Luo, T. Makino, C. Matsui, M. Morohashi, Calcitonin gene-related peptide upregulates melanogenesis and enhances melanocyte dendricity via induction of keratinocyte-derived melanotrophic factors, J. Invest. Dermatol. Symp. Proc., 1999, 4, 116–125.
C. M. Stefanato, M. Yaar, J. Bhawan, T. J. Phillips, M. G. Kosmadaki, V. Botchkarev, B. A. Gilchrest, Modulations of nerve growth factor and Bcl-2 in ultraviolet-irradiated human epidermis, J. Cutan. Pathol., 2003, 30, 351–357.
J. Hosoi, G. F. Murphy, C. L. Egan, E. A. Lerner, S. Grabbe, A. Asahina, R. D. Granstein, Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide, Nature, 1993, 363, 159–163.
R. C. Brooke, S. A. Newbold, N. R. Telfer, C. E. Griffiths, Discordance between facial wrinkling and the presence of basal cell carcinoma, Arch. Dermatol., 2001, 137, 751–754.
S. Halachmi, M. Yaar, B. A. Gilchrest, Advances in skin aging/photoaging: theoretical and practical implications, Ann. Dermatol. Venereol., 2005, 132, 362–367.
M. Toyoda, M. Hara, J. Bhawan, Epidermal innervation correlates with severity of photodamage. A quantitative ultrastructural study, Exp. Dermatol., 1996, 5, 260–266.
M. Toyoda, J. Bhawan, Electron-microscopic observations of cutaneous photoaging versus intrinsic aging, J. Geriatr. Dermatol., 1995, 3, 131–143.
I. Besne, C. Descombes, L. Breton, Effects of age and anatomical site on density of sensory innervation in human epidermis, Arch. Dermatol., 2002, 138, 1445–1450.
M. Kumakiri, K. Hashimoto, I. Willis, Biological changes of human cutaneous nerves caused by ultraviolet irradiation: an ultrastructural study, Br. J. Dermatol., 1978, 99, 65–75.
M. Kumakiri, K. Hashimoto, Cutaneous nerve stimulation by psoralen-ultraviolet A therapy: an ultrastructural study, J. Invest. Dermatol., 1978, 70, 163–172.
F. J. Legat, L. T. Jaiani, P. Wolf, M. Wang, R. Lang, T. Abraham, A. R. Solomon, C. A. Armstrong, J. D. Glass, J. C. Ansel, The role of calcitonin gene-related peptide in cutaneous immunosuppression induced by repeated subinflammatory ultraviolet irradiation exposure, Exp. Dermatol., 2004, 13, 242–250.
F. J. Legat, P. Wolf, L. T. Jaiani, R. Lang, M. S. Wang, C. A. Armstrong, J. C. Ansel, J. D. Glass, Increased intraepidermal CGRP correlates with local immunosuppression after repeated broadband and narrowband UVB, Exp. Dermatol., 2004, 13, 567–591 (Abstract, p. 585).
F. J. Legat, T. Griesbacher, R. Schicho, P. Althuber, R. Schuligoi, H. Kerl, P. Wolf, Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats, Neurosci. Lett., 2002, 329, 309–313.
A. Sleijffers, M. Herreilers, H. van Loveren, J. Garssen, Ultraviolet B radiation induces upregulation of calcitonin gene-related peptide levels in human Finn chamber skin samples, J. Photochem. Photobiol., B, 2003, 69, 149–152.
J. Wallengren, F. Sundler, Phototherapy reduces the number of epidermal and CGRP-positive dermal nerve fibres, Acta Dermatol. Venereol., 2004, 84, 111–115.
M. Nolano, D. A. Simone, G. Wendelschafer-Crabb, T. Johnson, E. Hazen, W. R. Kennedy, Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation, Pain, 1999, 81, 135–145.
V. A. Tron, M. D. Coughlin, D. E. Jang, J. Stanisz, D. N. Sauder, Expression and modulation of nerve growth factor in murine keratinocytes (PAM 212), J. Clin. Invest., 1990, 85, 1085–1089.
A. Marconi, C. Vaschieri, S. Zanoli, A. Giannetti, C. Pincelli, Nerve growth factor protects human keratinocytes from ultraviolet-B-induced apoptosis, J. Invest. Dermatol., 1999, 113, 920–927.
M. S. Fisher, M. L. Kripke, Systemic alteration induced in mice by ultraviolet light irradiation and its relationship to ultraviolet carcinogenesis, Proc. Natl. Acad. Sci. USA, 1977, 74, 1688–1692.
F. Rijken, R. C. Kiekens, P. L. Bruijnzeel, Skin-infiltrating neutrophils following exposure to solar-simulated radiation could play an important role in photoageing of human skin, Br. J. Dermatol., 2005, 152, 321–328.
V. A. Botchkarev, S. Eichmuller, E. M. Peters, P. Pietsch, O. Johansson, M. Maurer, R. Paus, 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.
M. A. Grimbaldeston, A. Simpson, J. J. Finlay-Jones, P. H. Hart, The effect of ultraviolet radiation exposure on the prevalence of mast cells in human skin, Br. J. Dermatol., 2003, 148, 300–306.
S. Bosset, M. Bonnet-Duquennoy, P. Barre, A. Chalon, R. Kurfurst, F. Bonte, S. Schnebert, B. Le Varlet, J. F. Nicolas, Photoageing shows histological features of chronic skin inflammation without clinical and molecular abnormalities, Br. J. Dermatol., 2003, 149, 826–835.
S. J. Galli, M. Tsai, B. K. Wershil, S. Y. Tam, J. J. Costa, Regulation of mouse and human mast cell development, survival and function by stem cell factor, the ligand for the c-kit receptor, Int. Arch. Allergy Immunol., 1995, 107, 51–53.
M. Toyoda, M. Nakamura, M. Morohashi, Neuropeptides and sebaceous glands, Eur. J. Dermatol., 2002, 12, 422–427.
L. Aloe, S. D. Skaper, A. Leon, R. Levi-Montalcini, Nerve growth factor and autoimmune diseases, Autoimmunity, 1994, 19, 141–150.
R. Levi-Montalcini, S. D. Skaper, R. Dal Toso, L. Petrelli, A. Leon, Nerve growth factor: from neurotrophin to neurokine, Trends Neurosci., 1996, 19, 514–520.
M. Steinhoff, N. Vergnolle, S. H. Young, M. Tognetto, S. Amadesi, H. S. Ennes, M. Trevisani, M. D. Hollenberg, J. L. Wallace, G. H. Caughey, S. E. Mitchell, L. M. Williams, P. Geppetti, E. A. Mayer, N. W. Bunnett, Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism, Nat. Med., 2000, 6, 151–158.
P. H. Hart, M. A. Grimbaldeston, J. J. Finlay-Jones, Sunlight, immunosuppression and skin cancer: role of histamine and mast cells, Clin. Exp. Pharmacol. Physiol., 2001, 28, 1–8.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Legat, F.J., Wolf, P. Photodamage to the cutaneous sensory nerves: role in photoaging and carcinogenesis of the skin?. Photochem Photobiol Sci 5, 170–176 (2006). https://doi.org/10.1039/b508856a
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1039/b508856a