PIGMENT CELL & MELANOMA Research Skin phototype: a new perspective Vittoria Maresca, Enrica Flori and Mauro Picardo

DOI: 10.1111/pcmr.12365 Volume 28, Issue 4, Pages 378–389

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Pigment Cell Melanoma Res. 28; 378–389

Skin phototype: a new perspective Vittoria Maresca, Enrica Flori and Mauro Picardo Laboratory of Cutaneous Physiopathology and Integrated Centre of Metabolomics Research, San Gallicano Dermatologic Institute, Rome, Italy

KEYWORDS phototype/melanocytes/MC1R/a-melanocyte-stimulating hormone/ultraviolet radiation

CORRESPONDENCE: M. Picardo, e-mail: [email protected]

PUBLICATION DATA Received 9 January 2015, revised and accepted for publication 16 March 2015, published online 18 March 2015 doi: 10.1111/pcmr.12365

Summary Cutaneous phototype is considered mainly related to cutaneous pigmentation and to the eumelanin/ pheomelanin ratio, which is mostly genetically determined by the melanocortin 1 receptor (MC1R) polymorphisms. However, data in literature indicate that, in addition to stimulation of eumelanin synthesis, the MC1R signalling activates antioxidant, DNA repair and survival pathways. New emerging aspects regarding photoprotection and skin phototypes are going beyond those features connected to the melanin content in the skin. Important new findings link the MC1R to nuclear receptors activation, shedding light on new extramelanogenic effects dependent on the a-melanocyte-stimulating hormone (a-MSH) activity and new ways through which such functions are modulated. These evidences indicate that several factors including melanin play a part in defining the basis for individual sun sensitivity, suggesting that the cutaneous phototype represents a ‘biochemical fingerprint’.

Introduction Skin phototype is a clinical classification system, developed by Thomas B. Fitzpatrick, based on self-reported erythema sensitivity and tanning ability (Fitzpatrick, 1988). The phototype is graded on a number (from I to VI) which, to some extent, reflects the degree of colour in the skin and its level of sensitivity to the damage generated by ultraviolet radiation (UV) (Del Bino and Bernerd, 2013; Fitzpatrick, 1988). Such classification has proven to be useful in indicating photoinduced skin cancer risk (Del Bino and Bernerd, 2013; Fitzpatrick, 1988; van der Leest  et al., 2011; Leiter and Garbe, 2008; Li et al., 2012; Mahe et al., 2011; dos Santos Silva et al., 2009). Constitutive skin colour designates a genetically determined level, type and distribution of melanin (Rouzaud et al., 2005; Sturm, 2009; Sturm et al., 2003), which is considered the main photoprotective agent against UV-induced deleterious effects (Kadekaro et al., 2003; Meredith and Sarna, 2006; Prota, 1997; Rouzaud et al., 2005). Several experimental data demonstrated that cutaneous pigmentation is regulated by a complex intercellular network, in which both keratinocytes and fibroblasts synthesize hormones, growth factors and cytokines, able to modulate melano cyte activity (Cardinali et al., 2008, 2012; Cario-Andre et al., 2006; Kovacs et al., 2010; Nordlund, 2007). More-


over, evidence suggests that skin phototype and the degree of photoprotection associated with it, is a complex strategy, in which melanins represent one of the elements (Bessou-Touya et al., 1998; Briganti et al., 2012;  et al., 1999, 2005; Maresca et al., 2006, Cario-Andre 2008, 2009; Picardo et al., 1999; Schallreuter and Wood, 2001). This review attempts to shed light on new aspects relating to the concepts of photoprotection and skin phototype, going beyond those aspects connected to the melanin content in skin and the filter effect carried out by it. Skin pigmentation: an adaptive characteristic of human skin One adaptive characteristic which is peculiar to human skin has been the gradual loss of hair on the body surface, linked to the appearance of skin pigmentation in the hairless areas (Jablonski and Chaplin, 2000, 2013). This event coincided with the transfer of Homo erectus from the African forests to the savannah. Travelling over long distances in sunny regions, these hominins needed to modify their way of thermoregulating. The first requirement was met by the number of sweat glands spread all over the body and the reduction of the body surface covered by hair. The second requirement of protecting the skull and therefore the brain from overheating, again due to solar exposure, was met by the concentration of ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

A new point of view of phototype

hair on the head (Ibraimov, 2007; Jablonski and Chaplin, 2000; Juzeniene et al., 2009; Pagel and Bodmer, 2003). After the hair had fallen out, human skin, which was initially light like that of current great apes (Jablonski and Chaplin, 2000; Westerhof, 2007), gradually began to pigment (Elias et al., 2009; Jablonski and Chaplin, 2000; Juzeniene et al., 2009). Various hypotheses, not mutually exclusive, have been formulated to explain which selective pressure caused the change. Some of them proposed that the gradual levels of pigmentation in different geographical areas of the world would be the evolutionary result of a compromise between skin which is light enough to allow the synthesis of vitamin D, essential for calcium absorption, yet still dark enough to protect the inner layers of skin from damage caused by UV (destruction of folic acid, one of the B-group vitamins) (Jablonski and Chaplin, 2000, 2013, 2014; Juzeniene et al., 2009; Yuen and Jablonski, 2010). Another hypothesis proposed was that human pigmentation developed to provide an effective permeability barrier, a requirement for life in desiccating terrestrial environment (Elias and Williams, 2013; Elias et al., 2009, 2010; Man et al., 2014). Experimental evidence shows that darkly pigmented skin possess a more efficacious skin barrier than lightly pigmented skin (Gunathilake et al., 2009; Liu et al., 2010; Man et al., 2014). Moreover, in depigmented areas of vitiligo, the epidermal barrier recovery after stripping is significantly delayed (Liu et al., 2010). Finally, pigmented hairless mice (Skh2) display a superior permeability barrier in comparison with the non-pigmented albino (Skh1) mice (Man et al., 2014). The barrier competence reflects a more cohesive structure of adjoining corneocytes, coupled with its low water content and its acidic pH, which encourages the growth of normal flora, while providing a formidable distal layer of the innate immune system that combats the invasion of pathogens. (Brogden et al., 2012; Drake et al., 2008; Elias, 2007; Elias and Williams, 2013; Gunathilake et al., 2009; Mackintosh, 2001). According to these disparate hypotheses, skin pigmentation is therefore an element which is closely linked to general skin homeostasis: not only a filter which protects the body from UV, but constituting an efficient barrier which prevents xerosis, protects against pathogens and indirectly contributes to thermoregulation. Melanogenesis: a biosynthetic means of providing protection, not only through the production of melanin Regulation of melanogenesis is a quite complex mechanism. Locally, keratinocytes and fibroblasts are involved through the production of proopiomelanocortins (POMCs), growth factors, cytokines and reactive oxygen species. Systemic hormones such as corticosteroids and oestrogens also influence the pigmentation process (Imokawa, 2004; Kondo and Hearing, 2011; Schallreuter et al., 2008; Yamaguchi and Hearing, 2009). The a-MSH/ MC1R interaction triggers cAMP/PKA signalling, the most ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

relevant pathway for melanin synthesis. Moreover, a-MSH is able to control melanogenesis also independently of MC1R, possibly by acting directly in melanosomes (Schallreuter et al., 2008). Among the other melanocortins, ACTH, the most abundant melanocortin in the human epidermis, interacts with MC1R and stimulates the phosphatidylinositol (PI(4,5)P2/PLC-beta) pathway and the intracellular release of calcium from the RER. The calcium release promotes the active transport of L-phenylalanine via large amino acid transporter 1 (LAT1) and its turnover via phenylalanine hydroxylase activity (PAH), in the presence of the cofactor 6BH4, providing sufficient concentrations of L-tyrosine to sustain melanogenesis (Schallreuter and Wood, 1999; Schallreuter et al., 2004). The correlation between epidermal PAH activities and 6BH4 levels with skin phototypes I-VI supports their close relationship with skin pigmentation (Schallreuter et al., 1994, 1997). The PI(4,5) P2/PLC-beta pathway controls also the activation of PKCb which in turn activates tyrosinase by phosphorylating serine residues in its cytoplasmic domain (Park et al., 1999). The same pathway is also activated by catecholamines (Grando et al., 2006). Following UV irradiation, p53 increases melanogenesis by inducing the expression of POMC in keratinocytes and by directly stimulating the genes encoding tyrosinase and tyrosinase-related protein-1 (TYRP-1) in melanocyte (Cui et al., 2007; Khlgatian et al., 2002; Kondo and Hearing, 2011; Nylander et al., 2000). Moreover, a mechanism involving H2O2 in the regulation of tyrosinase via p53 through the transcription of hepatocyte nuclear factor 1a has been proposed (Schallreuter et al., 2003). The nitric oxide (NO) produced in melanocytes after UV is considered as a major intra- and extracellular messenger molecule. NO elicits its effects through the activation of a soluble guanylate cyclase, leading to an increase in intracellular cGMP content and the activation of cGMPdependent protein kinase, stimulating melanogenesis (Busc a and Ballotti, 2000). Also H2O2, in the micromolar range, is able to act as a signal mediator, up-regulating a plethora of transcription factors including p53, MITF, NF-kB and the antioxidant enzymes catalase, thioredoxin reductase, glutathione reductase and methionine sulfoxide reductase (Schallreuter et al., 2008). DNA damage and DNA repair play relevant roles in the UV-induced melanogenic response of melanocytes. In particular, thymidine dimmers (pT-pT) increase p53 expression and up-regulate the expression of tyrosinase and TRP1 (Arad et al., 2006; Gilchrest and Eller, 1999). Finally, a number of new factors that are involved in melanogenesis have recently been reported, such as factors regulating melanosome pH and ion transport (Bellono and Oancea, 2014; Cheli et al., 2009; Fuller et al., 2001; Kondo and Hearing, 2011; Schallreuter et al., 2008). Research in the fields of pigmentation and dermatology essentially focuses on melanin as a filter, types of melanin (whether eu or pheomelanin) and the correlation 379

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with skin tumours in response to UV exposure. In particular, eumelanin, characteristic of darkly pigmented skin, acts as a filter against UV (d’Ischia et al., 2013; Kadekaro et al., 2003; Meredith and Sarna, 2006) and possesses scavenger properties towards the UV-induced free radical species (Kadekaro et al., 2003; Meredith and Sarna, 2006; Prota, 1997). On the other hand, pheomelanin, predominantly present in individuals with pale skin and red or fair hair, presents different properties, being a less effective filter against UV (Prota, 1997), and acting as an endogenous photosensitizer (Hill and Hill, 2000; d’Ischia et al., 2013; Kadekaro et al., 2003; Maresca et al., 2006; Prota, 1997; Rouzaud et al., 2005). Moreover, the interest in colourless intermediates of melanogenesis has traditionally been focused on their role as pigment precursors. However, specific melanin intermediates may exert, per se, a protective function not necessarily related to their capacity to act as filters (d’Ischia et al., 2013). The diffusible major intermediate in eumelanin biosynthesis 5,6-dihydroxyindole (DHICA) exerts an inhibitory effect against lipid peroxidation (Gauden et al., 2008; Memoli et al., 1997; Novellino et al., 1998, 1999; Zhang et al., 2000). On human keratinocytes, DHICA induces the antioxidant defence systems and differentiation and significantly reduces the UV-induced apoptosis (Kovacs et al., 2012). Therefore, DHICA mediates cell protection mechanisms in melanocytes and in the surrounding keratinocytes, functioning as a diffusible chemical messenger in the context of the paracrine interactions between epidermal cells, regulating skin homeostasis and defence. Moreover, melanin may protect against H2O2-induced DNA strand breaks in both melanocytes and keratinocytes and through its ability to bind Ca2+ (Hoogduijn et al., 2004).

MC1R: a key regulator of pigmentation The Melanocortin 1 receptor (MC1R) is the only member of the family of seven-transmembrane G-protein-coupled melanocortin receptors (MCRs) expressed on the membrane of melanocytes, with a key role in the regulation of €hm et al., pigmentation (Abdel-Malek et al., 2014; Bo n et al., 2014; Nasti and Timares, 2006; Garcıa-Borro 2014; Rouzaud and Hearing, 2005; Slominski et al., 2004; Sturm, 2002, 2009; Sturm et al., 2003). The activation of this receptor by a-melanocyte-stimulating hormone (a-MSH) or adrenocorticotropic hormone (ACTH), two peptidic hormones produced by keratinocytes and deriving from the processing of proopiomelanocortin, triggers a mechanism of signal transduction which involves the adenylyl-cyclase via Gs protein and leads to increased intracellular cAMP levels and activation of protein kinase-A (PKA). The cAMP/PKA signal transduction pathway is the main pathway responsible for the melanogenic actions of a-MSH (Busca and Ballotti, 2000; n et al., 2014; Im D’Orazio and Fisher, 2011; Garcıa-Borro et al., 1998). PKA phosphorylates the cAMP-responsive 380

element-binding protein (CREB) which in turn induces the microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte development, survival and differentiation (Cheli et al., 2010; Levy et al., 2006) and a key transcription factor for the expression of tyrosinase and TRP-1/TRP-2 (Bertolotto et al., 1998; Busc a and Ballotti, 2000; Cheli et al., 2010; Yamaguchi et al., 2007). In addition, upon a-MSH stimulation, MC1R activates the extracellular signal-regulated kinases (ERK) ERK1/ERK2 mitogen-activate protein kinase (MAPK) n et al., 2014; pathway (Busc a et al., 2000; Garcıa-Borro Herraiz et al., 2009), which also plays a key role in melanin synthesis, at least in part, through the regulation of MITF activation and stability (Englaro et al., 1998; n et al., 2014; Hemesath et al., 1998; Herraiz Garcıa-Borro et al., 2011; Wu et al., 2000). a-MSH-induced PKA activation also triggers the p38MAPK pathway, implicated in the regulation of important steps in melanocyte differentiation (Newton et al., 2007; Singh et al., 2005; Smalley and Eisen, 2000, 2002). Moreover, a-MSH signalling impinges on the peroxisome proliferator-activated receptor gamma coactivator proteins (PGC-1s), transcriptional coactivators of most of the nuclear receptors, and thereby playing important roles in numerous metabolic processes (Chinsomboon et al., 2009; Spiegelman, 2007; Yoon et al., 2001). The PKA-dependent activation of PGC1s is required for the induction of MITF transcription, providing an interesting link between metabolism and pigmentation (Ronai, 2013; Shoag et al., 2013). The finding that MITF also contributes to PGC-1a transcription suggests the existence of a feedback loop for regulation of the PGC-1a-MITF axis (Haq et al., 2013; Ronai, 2013; Vazquez et al., 2013). It is noteworthy that the transduction through cAMP/PKA pathway does not include only the activated MCIR but also other receptors such as b2adrenoceptor, the muscarinic receptors (M1, M3, M5), the a- and b-oestrogen receptors and the CRF/CRF-R1 signal (Schallreuter et al., 2008). Stimulation of MC1R induces the synthesis of photoprotective eumelanin. MC1R is highly polymorphic and its variants can explain differences in the wide range of human skin pigmentation. Melanocytes that express the consensus sequence for MC1R are darkly pigmented. However, more than 100 gene polymorphisms have been n et al., 2014; described (Chen et al., 2014; Garcıa-Borro rez Oliva et al., 2009), some of which have been Pe demonstrated to be loss-of-function variants (Herraiz et al., 2012; Sturm, 2009; Sturm et al., 2003). Some of these variants are closely associated with the red hair and fair skin phenotype (RHC-variants), a condition that is determined by the prevalent level of pheomelanin synthesis. This can place the individual at higher risk of malignant skin melanomas. MC1R: not only a regulator of pigmentation The information available about MC1R and its ligand a-MSH points to an interaction capable of coordinating ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

A new point of view of phototype

several homeostatic skin functions, which go well beyond the mere control of quantitatively and qualitatively photoprotective melanin (Abdel-Malek et al., 2014; Garcıan et al., 2014). The MCRs family actually represents Borro an old system of receptors, which are stimulated by derivatives of proopiomelanocortin (Abdel-Malek et al., €hm et al., 2006; Garcıa-Borro n et al., 2005, 2014; Bo 2014; Rouzaud and Hearing, 2005; Sturm, 2009). They are expressed in several tissues in man and other mammals. The members of this receptor family are involved in an extraordinarily diverse number of physiological functions, including pigmentation, energy homeostasis, exocrine secretion, inflammation and €hm et al., 2006; Catania, cardiovascular regulation (Bo 2007; Rodrigues et al., 2014; Slominski et al., 2004). Even though they are expressed in different cells and tissues, as G-protein-coupled receptors, they share the same ancestor pathways: the cAMP/PKA signal pathway and the phosphatidylinositol signal pathway, which do not always necessarily coexist under the same receptor (Collins et al., 1992; Dennis et al., 1991; Gilman, 1995; Irvine, 1992; Krumins and Gilman, 2006; Yang, 2011). Through these different transduction pathways, expressed in different tissues, they can promote similar protective strategies. Exposure of the skin to UV radiation induces the production of a-MSH by the keratinocytes, which, in turn, stimulate eumelanin synthesis and melanocyte survival and proliferation by binding and activating n et al., MC1R (Abdel-Malek et al., 2014; Garcıa-Borro 2014). a-MSH is also able to stimulate protective biological effects in non-melanocytic populations, such as keratinocytes and fibroblasts. These amelanotic systems provide information about potential photoprotective properties of a-MSH that go beyond its ability to regulate melanogenesis. In dermal fibroblasts, a-MSH binding to MC1R reduces the transforming growth factor (TGF-b1)€hm et al., induced synthesis of collagen types I and III (Bo 2004, 2006) and reduces skin fibrosis in mouse models of scleroderma (Kokot et al., 2009b). In keratinocytes, a-MSH enhances UV-induced DNA repair (Dong et al., 2010) and increases the expression of the transcription factors Nrfs, which exert a key regulatory role in the expression of ROS-detoxifying enzyme (Kokot et al., 2009a). Furthermore, the activation of the a-MSH/MC1R interaction has been implicated in the regulation of extracellular matrix homeostasis (Muffley et al., 2011). Finally, a-MSH is also known to exert anti-inflammatory effects in different cell populations, not only in the skin (Brzoska et al., 2008; Catania, 2007; Kokot et al., 2009a; Mastrofrancesco et al., 2010; Raap et al., 2003; Scholzen et al., 2003). MC1R: a regulator of oxidative stress and DNA repair Further emphasis has been given to the role of MC1R in controlling oxidative stress (Kadekaro et al., 2010; Maresca et al., 2010; Song et al., 2009) and in maintaining genomic integrity (Denat et al., 2014; Hauser et al., 2006; ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Kadekaro et al., 2012; Yin et al., 2014) in melanocytes. These two biological aspects are closely linked because oxidative stress, particularly when generated following UV exposure, is one of the main causes of DNA damage and one of the principal mechanisms which trigger cancer. a-MSH is able to counteract UV-induced oxidative damage by decreasing intracellular levels of hydrogen peroxide (Haycock et al., 2000; Kadekaro et al., 2005, 2010; Song et al., 2009) and enhances the repair of DNA photoproducts in primary cultures of human melanocytes €hm et al., 2005; Kadekaro et al., 2005, 2010; Smith (Bo et al., 2008; Song et al., 2009; Swope et al., 2014). Moreover, a-MSH increases phosphorylation of p53 in UVR-irradiated melanocytes, which, in turn, leads to p53 accumulation and activation. The increase in p53 is significant in reducing ROS generation, and consequently oxidative DNA damage, as well as in regulating the expression of enzymes that have a key role in base excision repair (BER), the main repair pathway for oxidative DNA damage (Denat et al., 2014; Kadekaro et al., 2012). Furthermore, the induction of the NR4A subfamily of nuclear receptors by MC1R signalling exerts a key role in promoting DNA repair in UV-irradiated melanocytes (Jagirdar et al., 2013; Smith et al., 2008; Yin et al., 2014). In addition, wild-type MC1R, but not its RHC-variants, significantly stabilizes the phosphatase and tensin homologue (PTEN) in UV-irradiated cells (Cao et al., 2013). In non-melanoma skin cancer, PTEN acts as an essential genomic gatekeeper through the regulation of the UV-induced DNA repair (Ming et al., 2011). Moreover, the interaction between MC1R and the b-arrestin (ARRB) family of cytosolic multifunctional adaptor proteins has been recently described (Abrisqueta et al., 2013), and b-arrestins are implicated in modulation of DNA damage signalling pathways (Hara et al., 2011). In association with melanin, the antioxidant defence system has to act in an integrated manner in order to minimize the damage caused by UV-generated free radicals within the cell (Briganti and Picardo, 2003). Some experimental evidence has shown a correlation between pigmentation and antioxidants. Thioredoxin reductase and catalase activities directly correlate with cutaneous phototype in different experimental models (Picardo et al., 1999; Schallreuter and Wood, 2001). In an ex vivo model of epidermal reconstructs, lightly pigmented reconstructs showed lower levels of catalase enzymatic activity and a higher concentration of peroxidable substrates in the cell membranes, in comparison with highly pigmented ones, making the first ones more susceptible to UV damage  et al., 1999; (Bessou-Touya et al., 1998; Cario-Andre Maresca et al., 2006). Among UV-generated reactive oxygen species, H2O2 plays a key role, both for its capacity to diffuse across cell membranes, reaching all cellular regions, and for its high reactivity (Bienert et al., 2006). In association with catalase, other antioxidant enzymes participate in the protection against oxidative stress. Thioredoxin reductase together with its electron 381

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acceptors thioredoxin, thioredoxin peroxidases and glutathione reductase/glutathione coupled to glutathione peroxidase are involved in the removal of hydrogen peroxide deriving from enzymatic dismutation of superoxide anion r, 2001; Schallrecatalysed by SOD (Nordberg and Arne uter and Wood, 2001; Schallreuter et al., 2008). Nevertheless, in melanocytes, the role of Cat is critical because it is the first enzyme devoted to the neutralization of H2O2 (Yohn et al., 1991). The enzyme is very susceptible to peroxidizing agents, recovers slowly when UV damaged (Shindo and Hashimoto, 1997; Shindo et al., 1994) and it can be considered a marker of both acute and chronic oxidative stress. In primary cultures of human melanocytes, catalase expression and activity are directly correlated with the total melanin content and tyrosinase expression (Maresca et al., 2008). The close relationship between melanogenic activity and protection from hydrogen peroxide provided by catalase suggested MC1R as the element capable of coordinating the two strategies. (Maresca et al., 2010). a-MSH increases the expression of catalase in unirradiated as well as UV-irradiated cells (Maresca et al., 2010; Song et al., 2009). Moreover, in response to a-MSH treatment, catalase is rapidly induced and colocalizes with the melanin in the melanosomes. The association with melanosomes suggests a role of this enzyme in the protection of melanocytes themselves and possibly of the whole skin against UV, through the transfer of melanosomes into keratinocytes (Maresca et al., 2010). The protective effects of a-MSH are absent in melanocytes expressing loss-of-function MC1R (AbdelMalek et al., 2014; Denat et al., 2014; Kadekaro et al., 2012; Smith et al., 2008; Song et al., 2009), establishing the significance of the activated MC1R in protection of melanocytes from oxidative stress. The a-MSH/nuclear receptors connection: a link of physiological relevance Relatively few genetic targets of MC1R signalling have been identified independent of the pigmentation pathway (Smith et al., 2008). Emerging evidence suggests that the nuclear receptors family of transcriptional regulators has a role in the context of melanocyte biology. MC1R activation induces the transcription of the NR4A subfamily of nuclear receptors (Jagirdar et al., 2013; Smith et al., 2008; Yin et al., 2014), implicated in a wide range of biological processes including cell proliferation, differentiation, metabolism, inflammation and vascular diseases (Pearen and Muscat, 2010; Smith et al., 2008; Yin et al., 2014). More recently, the involvement of NR4A proteins in promoting DNA repair in several cell types has been documented (Malewicz et al., 2011; Ramirez-Herrick et al., 2011; Smith et al., 2008). The induction of these nuclear receptors by MC1R activation in melanocytic cells seems to be a key component of MC1R-mediated DNA repair following UVR (Smith et al., 2008). We recently identified an activating connection between a-MSH and the peroxisome proliferator-activated receptor-c (PPAR-c) 382

(Maresca et al., 2013) in melanocytic cells. PPAR-c is a transcription factor belonging to the nuclear receptor family of peroxisome proliferator-activated receptors (PPARs). These transcription factors are activated by lipid mediators, such as linoleic acid or lipid products of lipoxygenases (Montagner et al., 2011; Varga et al., 2011; Wahli and Michalik, 2012). Three PPAR isoforms have been discovered and described in literature: a, b/d and c (Varga et al., 2011), all of which are expressed in human and mouse epidermis (Michalik and Wahli, 2007; Sertznig et al., 2008). In the skin, PPARs and corresponding ligands have been shown to regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses, redox state and wound healing (Dubrac and Schmuth, 2011; Park et al., 2013; Polvani et al., 2012; Sertznig et al., 2008; Varga et al., 2011). In particular, PPARc induces differentiation and increases cell antioxidant defence in response to natural or pharmacological agonists, in melanocytes and melanoma cells (Flori et al., 2011; Grabacka et al., 2008; Kang et al., 2004; Lee et al., 2007; Okuno et al., 2010; Polvani et al., 2012). Moreover, PPARc activation increases cell antioxidant defence and counteracts senescence-like phenotype in primary cultures of human fibroblasts (Briganti et al., 2013, 2014). Mice lacking epidermal PPARc exhibit a marked increase in photocarcinogenesis and heightened UVB-induced apoptosis, inflammation and barrier dysfunction (Sahu et al., 2012). Accordingly, mice with loss of the PPARc heterodimerization partner RXRa exhibit increased keratinocytes apoptosis and augmented DNA damage in response to UVB exposure (Wang et al., 2011). Due to its key role in the control of cell proliferation and differentiation, natural or pharmacological inductors of PPAR-c are used in innovative therapeutic models for various forms of cancer, including melanomas (Botton et al., 2009; Grommes €ssner et al., 2002; Robbins and Nie, 2012; et al., 2004; Mo Toyoda et al., 2002). The a-MSH/PPAR-c connection appears to be a phylogenetically preserved link. In fact, in the presence of a wild-type MC1R, it is independent of the animal species of origin and it is not correlated with the transformation condition of the cell (Maresca et al., 2013). Many of the functions modulated by PPAR-c pharmacological inductors overlap with functions modulated by a-MSH (e.g. control of inflammation, proliferation and redox state) for which the activation mechanism is not known. The detailed analysis of the a-MSH/nuclear receptors connection and the underlying pathways could shed light on new extra-melanogenic effects dependent on the a-MSH/MC1R interaction and new ways through which such functions are modulated (Figure 1). MC1R: a regulator of lipid signalling Research on the role of lipids in cell and tissue biology is a booming, groundbreaking field, especially because it has been understood that these molecules can initiate and regulate signalling events that will decisively influence ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

A new point of view of phototype POMCs

Figure 1. Summary of the protective effects induced by POMCs in melanocytes. The activation of MC1R by POMCs triggers different mechanisms of signal transduction (cAMP/PKA, ERK1/2, p38, PI(4,5)P2/PLCb), promoting the activation of key transcription factors (MITF and PPAR-c). This cascade of events leads to DNA repair and antioxidant defence promotion, in addition to stimulating pigmentation.

Activated signal transduction pathways

Activated transcription factors

POMCs-mediated protective effects

development, cellular differentiation, metabolism and related function through the regulation of gene expression (Varga et al., 2011; Wymann and Schneiter, 2008). Growing evidence suggests the involvement of lipids mediators in skin homeostasis. For example, the endocannabinoid system (ECS) plays a key role in the control of proliferation, differentiation, apoptosis and cytokine, mediator and hormone production in various cell types  et al., 2009). As regards of the skin and appendages (Bıro lipid-mediated signalling and melanocyte function, a fully functional ECS is present in human melanocytes and it stimulates melanogenesis through the activation of p38and p42/44 MAPK pathways (Pucci et al., 2012). Moreover, the sphingolipid-enriched total lipid fraction from human placenta induces pigmentation in melanocytic cells through p38 MAPK via induction of tyrosinase gene expression (Saha et al., 2006, 2009; Singh et al., 2005). However, the link between lipid mediators and MC1R is an unexplored topic. We demonstrated that the activation of PPAR-c in response to a-MSH depends on the induction of the phosphatidylinositol (PI(4,5)P2/PLCb) signal pathway (Maresca et al., 2013). This finding sums up a series of sporadic studies conducted in the past, in which the lipid pathway was indirectly postulated, but never clearly described, after the stimulation of cells with a-MSH (Buffey et al., 1992; Eves et al., 2006; Haycock et al., 2000). Lipids generated in the (PI(4,5)P2/PLCb) signal pathway, such as linoleic and arachidonic acids, are the main lipid mediators involved in signal transduction mechanisms (Robbins and Nie, 2012; Varga et al., 2011). When they are detached from the glycerol backbone of membrane phospholipids, they trigger cascade reactions mainly connected with the control of proliferation and inflammation (Yuri et al., 2007). Therefore, the (PI(4,5)P2/ PLCb) signal pathway could subtend the capacity of MC1R to influence, through lipid mediators, melanogenesis and other functions which include proliferation rates, control and inflammation. Moreover, the influence of fatty acid composition of the cell membranes has been, so far, only partially considered in association with the pigmentation levels and MC1R functionality (Picardo, 2009; Pucci ª 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd










et al., 2012; Saha et al., 2009), but instead it could be fundamental in driving manifold biological aspects. Finally, in recent years, alterations in lipid metabolism seem to be a common metabolic feature of malignant cells, including melanoma. These modifications are thought to promote pathology by generating substrates for energy production and membrane synthesis, as well as signalling lipids that €ller-Decker and trigger pro-tumorigenic cascades (Mu €rstenberger, 2007; Sertznig et al., 2008; Wymann and Fu Schneiter, 2008).

The biochemical fingerprint of phototype Cutaneous pigmentation is considered the major photoprotective mechanism against sun-induced skin ageing and carcinogenesis. Clinical evaluation of skin photosusceptibility is essentially based on the classification of Fitzpatrick skin phototype and minimal erythema dose (MED), which reflect, to some extent, the degree of colour in the skin (Fitzpatrick, 1988). However, data in literature shows that in depigmented vitiligo skin, the (sub)erythematogenic UV doses correlated with skin type of the patients (Briganti et al., 2012; Caron-Schreinemachers et al., 2005) and that subjects affected by albinism do not show a higher incidence of melanoma compared to subjects with red phenotypic features (Greaves, 2014), suggesting that melanin is not the only factor responsible for UV sensitivity. All the evidences which have been discussed in this review indicate that factors other than melanin determine a network of metabolic interactions which work together for the photoprotection of the skin and the correct construction of the barrier function. From a global and up-to-date point of view, all these parameters play a part in defining a biochemical basis for individual sun sensitivity. Eumelanin and pheomelanin are obviously crucial, with their quantitative and qualitative contribution to photoprotection (Kadekaro et al., 2003; Maresca et al., 2006; Meredith and Sarna, 2006; Prota, 1997; Rosso et al., 2007; Vincensi et al., 1998; Wakamatsu et al., 2006). The final products of eumelanogenesis and pheomelanogenesis, and the chemical intermediates of the 383

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two distinct biosynthetic pathways, contribute in different ways to promote photoprotection or alternatively to increase the phenomenon of cutaneous sun sensitivity (in the case of pheomelanin). Regarding eumelanogenesis, DHICA, due to its capacity to diffuse, is able to provide photoprotection also for keratinocytes, giving them antioxidant protection and promoting differentiation (Kovacs et al., 2012). In the case of pheomelanogenesis, different intermediates of this biosynthetic pathway in the hairs of red-haired subjects can be considered genetic markers associated with diverse gradations of ‘red’ phenotypes, with different photosensitizing potential. The endogenous photosensitising property commonly associated with pheomelanin reflects the capacity of this pigment to amplify the generation of free radicals, in response to exposure to UV radiation (Hill and Hill, 2000; Kadekaro et al., 2003; Maresca et al., 2006; Napolitano et al., 2014; Prota, 1997; Rouzaud et al., 2005). It is then the task of the chemical and enzymatic antioxidants, which collectively act as a ‘barrier’, to stop the reactivity of the free radicals which are produced in the skin following the impact of UV radiation and in particular of UVA (Briganti and Picardo, 2003; Natarajan et al., 2014). If, however, the UV dose is massive and/or the cutaneous antioxidant defence system is impaired, oxidative stress takes place, specific signal transduction pathways and cell cycle control elements are influenced and the initial steps of carcinogenesis are promoted (Godic et al., 2014; Sander et al., 2003). In association with melanins, antioxidants are therefore well placed to participate in skin photoprotection. The mechanisms to counteract, reduce or repair skin photodamage should also include DNA repair systems, extracellular matrix homeostasis and control of inflammatory effects. Although these biochemical parameters were not directly involved in determining skin colour nor in the filter effect against UV, they nonetheless influence a complete substrate responsible for photosensitivity.

Perspectives The information available in literature and the evidence, which will be added over time, are already sufficient to describe a point of view which is changing. For many years, diverse experimental evidence has been contributing to create a ‘biochemical fingerprint of cutaneous phototype’, which does not only include the contribution of melanin. In this respect, the study of MC1R may become extremely interesting, especially if it begins to be considered as more than just ‘the principle regulator of melanogenic enzymes’, but also as a member of the ‘MCR family’, that is a family of receptors which carry out different functions in cells and €hm et al., 2006; Catania, 2007; Rodrigues et al., tissues (Bo 2014; Slominski et al., 2004), functions which all produce cellular protection and well-being. As melanoma susceptibility is often related to the presence of ‘loss-of-function’ MC1R variants in some subjects’ genomes, what impor384

tance might the presence of one of these variants have in conditioning the response of PPAR-c, or in other aspects of cellular well-being? Knowledge of these aspects could broaden the concept of ‘loss of function’, related to MC1R, extending it to effects which are not exclusively pigmentary. Experimental evidences which have been reported in this review, together with other data present in literature and new evidence which will be added, are slowly modifying the concept of ‘phototype’, extending its meaning to biological and molecular parameters; therefore, no longer merely a clinical risk parameter for melanomas and other photoinducible diseases.

Acknowledgement lo€ıse Kerr-Wilson and Ms Lucia De Caprio for We thank Ms He language editing.

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Skin phototype: a new perspective.

Cutaneous phototype is considered mainly related to cutaneous pigmentation and to the eumelanin/pheomelanin ratio, which is mostly genetically determi...
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