Natallia E. Uzunbajakava,1Denise Falcone,2 and Gill Westgate3
1Philips Research, High Tech Campus 34, 5656 AE Eindhoven, The Netherlands
2Radboud University Medical Center, Department of Dermatology, René Descartesdreef 1, 6500 HB, The Netherlands
3Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, West Yorkshire, BD7 1DP, United Kingdom
The article ‘Blue Light and Its Effects on the Skin’ published in The Cosmetic Chemist on July 15, 2016 is a very good trigger to bring to light beneficial and therapeutic effects of both ultraviolet (UV) and visible radiation. As early humans evolved under the influence of the Sun’s radiation, they developed mechanisms both to efficiently utilize light to perform key physiological functions, such as vitamin D production, and to protect the body against excessive doses of this part of the electromagnetic spectrum through evolution of very dark skin as we developed a more hairless body. The migration of early humans into more northern climates resulted in a reduction of skin melanin levels, again influenced by the advantages of UV-induced production of vitamin D. What is less clear is whether our evolution ‘under the Sun’ means that our skin also responds to visible light in ways advantageous to healing, health, and well-being. UV, visible, and near- and far-infrared light has been used for decades for its therapeutic action, where a profound body of research on photomedicine and skin optics has been accumulated, all kick-started by pioneering work of Anderson and Parrish.2-4 In this letter we highlight some of the recent pearls and new developments in our knowledge on the therapeutic effect of light for skin and hair health and trends in photodermatology.
UV Light Therapy: A Safe Procedure?
Speaking of safety of UV light therapy, we would like to bring to attention an article by Henry W. Lim presented at the 23rd World Congress of Dermatology, held in Vancouver, Canada in 2015.5 Dr. Lim discussed data generated by the Dr. Jean Lee Lim team on 1,380 patients who were undergoing psoralen plus UVA (PUVA) therapy and subsequently had exposure to UVB light. The conclusion of the studies was that high UVB exposure levels (more than 300 treatments) confer a modest but significant increase in non-melanoma skin cancer risk in adults. Yet, overall, UVB therapy is substantially less carcinogenic than PUVA therapy. Research groups have stated that the presented data provide substantial reassurance that long-term treatment with UVB is reasonably safe, allowing us to consider UVB therapy a primary treatment option for patients with moderate-to-severe psoriasis.6
Are Home-use Light-based Devices the Future in Photodermatology?
Phototherapy has clear cost, and often efficacy and tolerance benefits over biologics, where the annual spending is $3,000 to $7,000 USD versus $27,000, respectively.5 The most recent trend in photodermatology is that phototherapy is clearly finding its way from the dermatologist's office to the homes of patients, as office therapy is often accompanied by low compliance due to lack of accessibility and the required time commitment by the patients.5 Obviously, home-based treatments do not bare these disadvantages. In addition, the cost of hospital-administered UV-light treatments is around ten-fold lower with a home-use device, which could cost $600-$2,000.7-9 More information on home UV-based phototherapy can be found elsewhere.7,8,10,11,12 Such benefits need to be realized commercially under the influence of the increases in scientific knowledge and in terms of the risk-benefit ratio in relation to the disease/disorder and intended outcome.
UV Light and Health Benefits
While not diminishing the negative effects that UV light could bring to the skin in the form of photoageing and cancer, one should not ignore that a latitude gradient exists for many autoimmune diseases (e.g., multiple sclerosis and type 1 diabetes) with greater disease incidence and prevalence occuring in regions further from the equator. In his keynote lecture at the 2015 European Society for Photobiology, Professor Prue H. Hart, Head of Inflammation Laboratory at Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, shared that in humans there have been many association studies on autoimmune diseases in patients with low vitamin D levels. Trials exploring the relationship between vitamin D and multiple sclerosis, diabetes, cardiovascular disease, and acute respiratory diseases are available or ongoing. In multiple sclerosis, increased incidence, prevalence, severity, and exacerbations of the disease have been associated with low serum vitamin D. At the same time, Professor Hart mentioned that it was shown that, when using vitamin D supplement, only 15% improvement in diseases was observed, questioning the value of supplementation.
All this draws attention to the importance of a better understanding of the positive effects of UV light for skin and health benefits, and to how one could achieve these benefits, while minimizing DNA and protein photo-damage, which would otherwise result in premature skin ageing and risk of cancer. The American and the European Society for Photobiology meetings are great events where the most recent insights on photobiology, including its fundamental and clinical aspects, are shared.
Discovery of New Phototransduction Mechanisms
It is of interest that, in parallel with investigations of safety and therapeutic actions of UV light, fundamental research studies are still being conducted to understand mechanisms responsible for melanin production. It is known that UVB causes DNA lesions, which leads to transcriptional activation of melanin-producing enzymes and, finally, results in delayed skin pigmentation that occurs in a matter of days. In contrast, UVA causes primarily oxidative damage and leads to immediate pigment darkening (IPD) within minutes, via a mechanism that until recently remained unknown.
Recent pioneering research, by the group of Dr. E. Oancea at Brown University in the United States, identified a receptor protein directly mediating phototransduction of UV light by primary human epidermal melanocytes (HEM), which results in a subsequent increase in melanin content. Dr. Oancea demonstrated in a series of publications that primary HEM express one of the opsins, rhodopsin, which upon interaction with UV light causes retinal-dependent calcium mobilization and early melanin synthesis.14 These findings identify a novel UV-sensitive signaling pathway in melanocytes, which may underlie the mechanism of IPD in human skin, which was proposed to be essential for protection of folates against photodegradation.15
Continuing the conversation about new knowledge on physiologically-relevant phototransduction in the skin via opsin photoreceptors, a very recent article by de Assis et al. revealed how opsins and circadian clock machinery can be altered in healthy versus malignant melanocytes and how this data could be used in the development of new pharmacological approaches of depigmentation diseases and skin cancer.16
From UV to Blue – Shifting a Therapeutic Window
Blue light (400-495 nm) corresponds to the spectral distribution of both violet (400-450 nm) and blue (450-495 nm) light. New research developments have influenced UV radiation specificity with a shifting of the well-accepted UV therapeutic window to a UV-free blue spectral range.
A clinical study at Radboud University Nijmegen Medical Centre in Nijmegen, The Netherlands, demonstrated that administration of blue light (450 nm), on a relative short-term skin therapy, does not cause DNA damage or premature photoaging.17 Following this safety study, Liebmann et al. demonstrated beneficial effects of blue optical radiation in the treatment of the symptoms of psoriasis vulgaris, a dermatological disease of immune nature, characterized by infiltrates of T cells and hyperproliferation of epidermal keratinocytes. Using in vitro cell cultures as model systems, it was shown that a defined dose of 450 nm light has pro-apoptotic effect on T cells, while it acts in an anti-proliferative way on epidermal keratinocytes, without signs of apoptosis.18 These studies paved the way for a blue light-based home-use medical device for the treatment of the symptoms of psoriasis vulgaris, whose in vivo clinical efficacy and safety in patients was demonstrated in clinical studies.19,20 Earlier this year, blue light (450 nm) was shown to be safe and effective in clinical studies on patients with eczema.21
The results confirm that UV-free blue light is effective and safe for treating chronic skin inﬂammation, such as psoriasis or atopic dermatitis. They are also substantiated by Fischer et al. who demonstrated that blue light irradiation at high and low doses resulted in a reduced ability of dendritic cells to release cytokines upon activation with strongest effects at higher doses. In co-cultures with CD4+ T cells, the overall reduced secretion of tested cytokines, except for IL-4, indicates that blue light not only reduces the capability of dendritic cells to stimulate T cells, but actively induces an anti-inﬂammatory milieu.22
Becker et al., using gene expression studies on keratinocytes, further demonstrated an anti-inflammatory effect of blue light. In particular, pathways or biological processes which were connected to anti-inflammatory responses were downregulated. Interestingly, blue light has also been shown to affect steroid hormone biosynthesis as well as the melanoma pathway, which contained significantly downregulated genes following blue light exposure.23 In addition, dose- and time-dependent downregulation of pathways playing a role on alopecia areata were observed after blue light treatment.24 The anti-inflammatory effect of blue light could perhaps be further extended to its therapeutic use not only in the dermatological field, but also for systemic conditions such as arthritis and cardiovascular diseases.
As fundamental investigation of non-UV light-induced phototransduction continues, Buscone et al., Uzunbajakava et al., and Siiskonen et al. demonstrated expression of cryptochromes and opsins in hair follicle compartments, primary human epidermal keratinocytes, dermal fibroblasts, and mast cells.25-27 As the absorption spectra of cryptochromes and opsins cover the blue-red spectrum, they could potentially mediate effects of light, leading to distinct physiological reactions. Indeed, Buscone and coworkers demonstrated that modulation of cryptochromes, blue light absorbing photoreceptors, had an impact on the hair growth phase in ex vivo human hair follicle culture, and thus they (cryptochromes) could potentially mediate blue light-induced therapeutic effects on hair- and skin cells.
A summary of potential phototransduction mechanisms and photoreceptors in human skin and hair follicles was recently published by Mignon et al., specifically in relation to photobiomodulation as a therapy for skin and hair disorders, revealing ‘a therapy full of promise, but a literature full of confusion.’28
To conclude, it is difficult to overestimate a potential positive role of blue- and visible light-based therapies for skin, hair, and, possibly, systemic health conditions, such as arthritis or cardiovascular disease, as several reports already demonstrated its safety and clinical efficacy in home-based medical devices for cutaneous disorders,18-22 and its potential positive impact on other health conditions.23-28 It is clear, however, that both fundamental research and well-designed clinical studies are needed to make a large leap in this so much aspired direction. Last but not least, scientific teams seeking therapeutic light-based solutions could benefit from embracing recent knowledge on candidate genes underlying cutaneous and systemic conditions, where building upon the results of the genome-wide association studies (GWAS) has already given a rise to promising drug-based therapies for alopecia areata—a hair loss condition autoimmune in nature.29-31
1. The Cosmetic Chemist Staff, Blue Light and its Effects on the Skin, The Cosmetic Chemist, www.TheCosmeticChemist.com, July 15 (2016).
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3. J.A. Parrish, Phototherapy and photochemotherapy of skin diseases, J. Invest. Dermatol., 77, 167-171 (1981).
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5. H.W. Lim, Phototherapy in dermatology: A call for action, J. Am. Acad. Dermatol, 72, 1078-1080 ( 2015).
6. J.L. Lim and R.S. Stern, High levels of ultraviolet B exposure increase the risk of non-melanoma skin cancer in psoralen and ultraviolet A-treated patients, J. Invest. Dermatol., 124, 505-513 (2005).
7. H. Cameron, S. Yule, R.S. Dawe, S.H. Ibbotson, H. Moseley, and J. Ferguson, Review of an established UK home phototherapy service 1998-2011: Improving access to a cost-effective treatment for chronic skin disease, Public Health, 128, 317-324 (2014).
8. A.N. Rajpara, J.L. O’Neill, B.V. Nolan, B.A. Yentzer, and S.R. Feldman, Review of home phototherapy, Dermatol. Online J., 16, 2 (2010).
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12. R. Hung, S. Ungureanu, C. Edwards, B. Gambles, and A.V. Anstey, Home phototherapy for psoriasis: a review and update, Clin. Dermatol., 40, 827-833 (2015).
13. P.H. Hart, Sunlight-induced immunosuppression – How much is attributable to vitamin D? European Society for Photobiology Congress, Aveiro, Portugal, Aug. 31 - Sept. 4 (2015).
14. N.L. Wicks, J.W. Chan, J.A. Najera, J.M. Ciriello, and E. Oancea, UVA phototransduction drives early melanin synthesis in human melanocytes, Curr. Biol., 21, 1906-1911 (2011).
15. J. Moan, K.P. Nielsen, and A. Juzeniene, Immediate pigment darkening: its evolutionary roles may include protection against folate photosensitization, FASEB J., 26, 971-975 (2012).
16. L.V. de Assis, M.N. Moraes, S. da Silveira Cruz-Machado, and A.M. Castrucci, The effect of white light on normal and malignant murine melanocytes: A link between opsins, clock genes, and melanogenesis, Biochim. Biophys. Acta, 1863(6 Pt A), 1119-1133 (2016).
17. M.M. Kleinpenning, T. Smits, M.H. Frunt, P.E. van Erp, P.C. van de Kerkhof, and R.M. Gerritsen, Clinical and histological effects of blue light on normal skin, Photodermatol. Photoimmunol. Photomed., 26, 16-21 (2010).
18. J. Liebmann, M. Born, and V. Kolb-Bachofen, Blue-light irradiation regulates proliferation and differentiation in human skin cells, J. Invest. Dermatol., 130, 259-269 (2010).
19. S. Pfaff, J. Liebmann, M. Born, H.F. Merk, and V. von Felbert, Prospective randomized long-term study on the efficacy and safety of UV-free blue light for treating mild psoriasis vulgaris, Dermatology, 231, 24-34 (2015).
20. A. Weinstabl, S. Hoff-Lesch, H.F. Merk, and V. Velber, Prospective randomized study on the efficacy of blue light in the treatment of psoriasis vulgaris, Dermatology, 223, 251-259 (2011).
21. K. Keemss, S.C. Pfaff , M. Born, J. Liebmann, H.F. Merk, and V. von Felbert, Prospective, randomized study on the efficacy and safety of local UV-free blue light treatment of eczema, Dermatology, Epub ahead of print (2016).
22. M.R. Fischer, M. Abel, S. Lopez Kostka, B. Rudolph, D. Becker, and E. von Stebut, Blue light irradiation suppresses dendritic cells activation in vitro, Exper. Dermatol., 22, 554-563 (2013).
23. A. Becker, C. Sticht, H. Dweep, F. van Abeelen, and N. Gretz, Oversluizen G: Impact of blue LED irradiation on proliferation and gene expression of cultured human keratinocytes, Proc. SPIE, 9309, 930909 (2015).
24. A. Becker, A. Klapczynski, N. Kuch, F. Arpino, K. Simon-Keller, C. de La Torre, C. Sticht, F.A. van Abeelen, G. Oversluizen, and N. Gretz, Gene expression profiling reveals aryl hydrocarbon receptor as a possible target for photobiomodulation when using blue light, Sci. Rep., accepted for publication (2016).
25. S. Buscone, B. Raafs, M. van Vlimmeren, A. Mardaryev, N.E. Uzunbajakava, and N.V. Botchkareva, A new path in defining light parameters for hair growth: Discovery and modulation of light sensitive receptors in human hair follicles. Lasers Surg. Med., 48, 29 (2016).
26. N.E. Uzunbajakava, I. Castellano, C. Mignon, S. Buscone, D.J. Tobin, N.V. Botchkareva, and M.J. Thornton, Human skin and hair can see light: Unravelling expression of photoreceptors towards improved light therapies for hair and skin disorders, Lasers Surg. Med., 48, 30 (2016).
27. H. Siiskonen, S. Buscone, I. Castellano Pellicena, A. Smorodchenko, N.E. Uzunbajakava, N.V. Botchkareva, M. Maurer, and J. Scheffel, Human skin mast cells express photoreceptors, 46th European Society for Dermatological Research, Munich, Germany (2016).
28. C. Mignon, N.V. Botchkareva, N.E. Uzunbajakava, and D.J. Tobin, Photobiomodulation devices for hair regrowth and wound healing: A therapy full of promise but a literature full of confusion, Exp. Dermatol., Epub ahead of print (2016).
29. A. Jabbari, J.E. Cerise, J.C. Chen, J. Mackay-Wiggan, M. Duvic, V. Price, M. Hordinsky, D. Norris, R. Clynes, and A.M. Christiano, Molecular signatures define alopecia areata subtypes and transcriptional biomarkers, EBioMedicine, 7, 240-247 (2016).
30. A. Jabbari, Z. Dai, L. Xing, J.E. Cerise, Y. Ramot, Y. Berkun, G.A. Sanchez, R. Goldbach-Mansky, A.M. Christiano, R. Clynes, and A. Zlotogorski, Reversal of alopecia areata following treatment with the JAK1/2 inhibitor baricitinib, EBioMedicine, 2, 351-355 (2015).
31. S. Heilmann-Heimbach, L.M. Hochfeld, R. Paus, and M.M. Nöthen, Hunting the genes in male-pattern alopecia: how important are they, how close are we and what will they tell us? Exp. Dermatol., 25, 251-257 (2016).