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What do the results mean? dermatology journals: a literature-based study. Dermatology, University of Nottingham: Estimating disease prevalence in the 50 Arch Dermatol 146:534–41 Nottingham, UK, 1–158 US states may sound a bit dull to some Mar A, Marks R (2000) Prevention of atopic Schram M, Spuls P, Williams H (2010) Is there readers, but quantifying such burden dermatitis. In: Williams HC (ed) Atopic a rural/urban gradient for atopic eczema? A Dermatitis. Cambridge University Press: systematic review. Br J Dermatol 162:964–73 of disease is a crucial step in planning Cambridge, UK, 205–20 Shaw TE, Currie GP, Koudelka CW et al. (2011) appropriate services, especially if such Odhiambo JA, Williams HC, Clayton TO et al. Eczema prevalence in the United States: data data can be coupled with disease sever- (2009) Global variations in prevalence of from the 2003 National Survey of Children’s ity and health-care usage (Chren and eczema symptoms in children from ISAAC Phase Health. J Invest Dermatol 131:67–73 Weinstock, 2004). The data thus pro- Three. J Allergy Clin Immunol 124:1251–8 Snyder, JP (1993) Flattening the Earth: 2000 Years vide the most basic of building blocks Peters TJ, Golding J (1987) The epidemiology of of Map Projections. Chicago, IL: University of Chicago Press, 33 for a Needs Assessment of National and childhood eczema: II. Statistical analyses to identify independent early predictors. Paediatr Williams HC (2003) Race vs ethnicity in State dermatology services for young Perinat Epidemiol 1:80–94 dermatology [reply]. Arch Dermatol 139:540 people (Schofield et al., 2009). Second, Rodríguez E, Baurecht H, Herberich E et al. (2009) Williams HC, Pembroke AC, Forsdyke H et al. the variation in disease prevalence with Meta-analysis of filaggrin polymorphisms in (1995) London-born black Caribbean children factors such as geographical location, eczema and asthma: robust risk factors in atopic are at increased risk of atopic dermatitis. J Am ethnic group, and educational status, if disease. J Allergy Clin Immunol 123:1361–70 Acad Dermatol 32:212–7 true, signals that the environment is criti- Schofield JK, Grindlay D, Williams HC (2009) Williams H, Stewart A, von Mutius E et al. (2008) Skin Conditions in the UK: A Health Care Is eczema really on the increase worldwide? cal for determining disease expression in Needs Assessment. Centre of Evidence-Based J Allergy Clin Immunol 121:947–54 eczema. Although genetic factors such as filaggrin gene mutations help to explain some variation in eczema (Rodríguez et al., 2009), it is likely that interaction with See related article on pg 188 environmental factors plays a critical role given the associations shown in this Urocanic Acid in the Skin: study and the increasing prevalence of disease over the past 20 years (Williams A Mixed Blessing? et al., 2008). The study findings do not mean that a young, black, well-educat- Neil K. Gibbs1 and Mary Norval2 ed, English-speaking resident of a city on the East Coast of the United States will Located in the stratum corneum, urocanic acid is a major epidermal chromophore necessarily get eczema, because these for UVR. This simple molecule has attracted a great deal of research interest over the associations relate to aggregated risks past half century, initially as a putative “natural sunscreen” and later as a mediator of and because they refer to attributes that photoimmunosuppression with a consequent role in photocarcinogenesis. For the point to more specific exposures such as first time, Barresi and colleagues provide robust evidence for the photoprotective diet, hygiene, and health behaviors. The role of endogenous urocanic acid and reopen the debate on the relative “benefi- challenge now is to identify the environ- cial” and “detrimental” properties of this molecule. mental factors that are amenable to pub- Journal of Investigative Dermatology (2011) 131, 14–17. doi:10.1038/jid.2010.276 lic health manipulation in the hope that this knowledge will bring us one step closer to eczema prevention (Mar and Urocanic acid (UCA) was originally iso- UCA in the liver, is absent in the skin, Marks, 2000). lated from the urine of a dog by Jaffé in which allows accumulation of UCA up 1874, but the presence of epidermal to 0.5% of the dry weight of the epider- CONFLICT OF INTEREST UCA was only confirmed in the 1950s. mis. In humans, epidermal UCA levels The author has worked with the International Study 2 of Asthma and Allergies (http://isaac.auckland. Trans-UCA is produced in the mam- range from 4 to 34 nM/cm and do not ac.nz) for the past 14 years. malian stratum corneum by the action correlate with any parameter so far tested of l-histidine ammonia lyase (histidase; including age, sex, pigmentation, skin References Hal) on histidine. The major source of phototype, and minimal erythema dose Brenninkmeijer EE, Schram ME, Leeflang MM et al. histidine in this skin compartment is fil- (see, for example, de Fine Olivarius et (2008) Diagnostic criteria for atopic dermatitis: a systematic review. Br J Dermatol 158:754–65 aggrin (formerly called histidine-rich al., 1997). UCA has been proposed as the Chren MM, Weinstock MA (2004) Conceptual protein) and reduced production of major acid–base regulator in the epider- issues in measuring the burden of skin diseases. filaggrin­ results in lower levels of UCA. mis, although recent results demonstrate J Investig Dermatol Symp Proc 9:97–100 Urocanase, the enzyme that catabolizes that the filaggrin–histidase–UCA cascade Johansson SG, Bieber T, Dahl R et al. (2004) Revised nomenclature for allergy for global use: report of the Nomenclature Review Committee of the 1Dermatological Sciences, University of Manchester, Manchester, UK and 2Biomedical Sciences, World Allergy Organization, October 2003. University of Edinburgh Medical School, Edinburgh, UK J Allergy Clin Immunol 113:832–6 Correspondence: Neil K. Gibbs, Dermatological Sciences, University of Manchester, Manchester Langan S, Schmitt J, Coenraads PJ et al. (2010) The Academic Health Sciences Centre, Stopford Building, Oxford Road, Manchester M13 9PT, UK. reporting of observational research studies in E-mail: [email protected]

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is not essential for the acidification of the From 1983 to date, research on UCA, with is a constitutive photoprotectant that surface of the stratum corneum (Fluhr et a few exceptions, has been dedicated to should reduce some major deleterious al., 2010). understanding its role in photoimmuno- UVR-induced effects by 33%. suppression and how this may increase The action spectrum for UVR-induced photocarcinogenic risk. As a conse- erythema in mammalian skin closely Beneficial photo quence, the putative photoprotective role resembles that for T^T induction and protection by of UCA has not been considered a topic erythemal responses are exaggerated if of much relevance or interest until now. repair of these lesions is deficient, such exogenous urocanic Early photoprotection experiments as in certain xeroderma pigment­osum acid contrasts with in guinea pigs, and more recently in complementation groups. It would there- its detrimental humans, have demonstrated that photo- fore be expected that the protection protection offered by topical application offered by endogenous­ UCA against |photoimmuno­ of UCA is limited and approximately T^T, as demonstrated by Barresi and suppressive effects. equivalent to a sunscreen with a sun pro- colleagues (2011), would translate to pro- tection factor (SPF) of 1.5. However, in tection against erythema. Interestingly, these types of studies, exogenous UCA the authors did not note any gross It was also established more than 50 was administered above the UCA already differences in skin pathology between the years ago that UCA is a major epidermal existing in the stratum corneum, so the histidinemic and wild-type mice 24 hours chromophore for UVR, which convinced efficacy of UCA as an endogenous pho- after irradiation. One study examining investigators that the molecule existed toprotectant per se was not assessed. the relationship between cutaneous UCA in the stratum corneum as a “natural Barresi and colleagues (2011, this issue) levels and erythemal photo­sensitivity sunscreen” (Tabachnick, 1957). As the elegantly address this question using mice in humans found that, despite a 10-fold photochemical properties and impor- that are histidase-deficient because of a variation in UCA concentration, there tance of DNA became understood, the mutation in the Hal gene. These histidin­ was no correlation between these two fact that the UCA absorption spectrum emic animals have less than 10-fold the parameters (de Fine Olivarius et al., partially overlapped the DNA absorption concentration of UCA in their stratum 1997). This is surprising because a strong spectrum added credence to this idea corneum than wild-type mice. Although inverse relationship would be expected and led the cosmetics industry to include a strain of histidase-deficient mice was between the concentration of UCA and UCA in their skin products. This remained available in the past (they were men- UVR transmission if UCA was acting the situation for the following quarter of a tioned in de Fabo and Noonan, 1983), purely as a chemical sunscreen in the century, which saw significant advances these animals were sickly and did not stratum corneum, and it suggests that in UCA photochemistry; it became clear breed well. Barresi and colleagues’ study UCA is acting in a more complex manner. that trans-UCA could be photoisomer- used animals resulting from a backcross Indeed, it has been variously reported that ized to cis-UCA on UVR exposure and between these original “Peruvian” mice UCA can also photosensitize DNA dam- this conversion was considered a “safe” and C57BL/6 mice, which has provided a age such as 6-4 photoproducts in vivo way to disperse photon energy. The pho- healthier histidinemic strain. The authors or cyclobutane adducts in vitro. Recent toisomerization reaction was reversible demonstrate that after broadband UVB evidence suggests that treatment of cells and both UCA isomers had very simi- irradiation of 250 mJ cm−2 (which is likely with cis-UCA can produce oxidative lar absorption properties. Such findings to represent an erythemal dose), the lev- DNA damage (8-oxo-deoxyguanosine) enhanced UCA’s reputation as an ideal els of DNA damage (thymine dimers; via the induction of intracellular reactive natural sunscreen. T^T) and markers of apoptosis (caspase-3 oxygen species (ROS; Sreevidya et al., This “understanding” of the role of and TUNEL) were about 40% higher 2010). In keratinocyte­ cultures cis-UCA epidermal UCA was shattered with in the epidermis of the histidinemic induced genes associated with apopto- the seminal finding that UCA was a mice than in wild-type animals. The sis, cell growth arrest, and oxidative stress chromophore­ for, and cis-UCA a media- photosensitivity of the histidinemic mice (Kaneko et al., 2008). The comparative tor of, the immunosuppressive effects of to T^T induction could be abrogated by contributions of these opposing mecha- UVR in the skin (de Fabo and Noonan, the topical application of a high concen- nisms to the erythemal response merit 1983). Subsequent work by other groups tration of UCA. further investigation. confirmed the original finding, which Thus, for the first time, a photopro- The implications of the findings of prompted de Fabo and Noonan to sub- tective role for endogenous UCA has Barresi and coworkers (2011) for photo­ mit a citizens’ petition in 1991 requesting been demonstrated in mammalian skin. immunosuppression­ are intriguing. the US Food and Drug Administration to Quantitatively, the protection is similar Experiments in mice reveal that find that “urocanic acid is a deleterious to that afforded by topical UCA applied removing or enhancing the repair of substance and may render any cosmetic exogenously in the mouse and human UVR-induced T^T, using photolyase or product containing it injurious.” A review studies conducted—an SPF of about T4 endonuclease, reduces photoim- by the US Cosmetic Ingredient Review 1.5—which at first glance may seem munosuppression, thus suggesting a Expert Panel and the gradual removal of small. However, unlike the vagaries of protective role for endogenous UCA in UCA from cosmetic products followed. sunscreen application, endogenous UCA this pathway. In contrast, cis-UCA is an

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the simultaneous increase in the level of cis-UCA, which is known to enhance photocarcinogenesis (Beissert et al., 2001). The contributions of cis-UCA- induced intracellular ROS formation (Sreevidya et al., 2010) and the recently reported ability of cis-UCA to induce the apoptosis of tumor cells through intracellular­ acidification (Laihia et al., 2010) should be taken into account when attempting to unravel the very confusing overall contribution of UCA to the photocarcinogenic­ process.

Summary The evidence presented by Barresi and colleagues (2011) suggests that trans- UCA acts as a natural sunscreen, giving lifelong, low-level protection against UVR-induced DNA damage and exces- sive keratinocyte apoptosis. However, Figure 1. Putative “beneficial” and “detrimental” effects of urocanic acid (UCA). (a) trans-UCA is cis-UCA, in addition to its well-reported formed in the stratum corneum from histidine (HIST) released from filaggrin; (b) exogenous trans-UCA immunosuppressive properties, may also absorbs UVR and protects against thymine dimer formation in keratinocytes; (c) cis-UCA is formed by initiate intracellular ROS production, photoisomerization of trans-UCA; (d) acting through membrane receptors, cis-UCA induces intracellular oxidative DNA damage, and cell reactive oxygen species (ROS) and hence oxidative DNA damage (8-oxo-dG); (e) cis-UCA initiates signaling that may negate any photo­ translation of genes associated with apoptosis and immunosuppression through direct signaling and protective effect (Figure 1). There is an cis intracellular ROS formation; and (f) -UCA provides proapoptotic intracellular acidification in tumor obvious need to examine the relative cells. SPF, sun protection factor, T^T, thymine dimers. susceptibility of wild-type and histidine- mic mice to photo­immunosuppression immunosuppressant. A report that intra­ important when its role in photocarcino­ and photo­tumorigenesis and also to cellular ROS may be induced by cis-UCA genesis is considered. assess the relevant photoresponses in (Sreevidya et al., 2010) may explain what The derived action spectrum for histidinemic humans. initially seemed a strange finding that nonmelanoma skin cancer in humans CONFLICT OF INTEREST an antioxidant (N-acetylcysteine) could (SCUP-h) closely mirrors that for The authors state no conflict of interest. reduce the immunosuppressive effects epidermal T^T formation. Barresi and of topically applied cis-UCA (Hemelaar coworkers (2011) clearly show that UCA ACKNOWLEDGMENTS and Beijersbergen van Henegouwen, protects against the production of T^T, so NKG thanks the British Skin Foundation for funding 1996). UCA therefore appears to be the presence of UCA would be expected his recent work on urocanic acid. protecting against T^T-mediated immu- to protect against photocarcinogenesis. References nosuppression at the same time that However, several studies have shown Barresi C, Stremnitzer C, Mlitz V et al. (2010) it is producing cis-UCA, which is an no difference in cutaneous UCA content Increased sensitivity of histidinemic mice immunosuppressant, and also possibly between those subjects with a past to UVB radiation suggests a crucial role of endogenous urocanic acid in photoprotection. inducing oxidative DNA damage, whose history of nonmelanoma skin cancer or J Invest Dermatol 131:188–94 immunosuppressive role is unclear. It cutaneous malignant melanoma and Beissert S, Ruhlemann D, Mohammad T et al. is probably no surprise that the action healthy controls. (2001) IL-12 prevents the inhibitory effects of spectrum for the UV-induced systemic Although the experiment comparing cis-urocanic acid on tumor antigen presentation suppression of contact hypersensitivity in photocarcinogenesis in wild-type by Langerhans cells: implications for photocarcinogenesis. J Immunol 167:6232–8 mice (de Fabo and Noonan, 1983) cor- and histidinemic mice has not yet de Fabo EC, Noonan FP (1983) Mechanism of relates with neither the action spectrum been reported, existing evidence immune suppression by ultraviolet irradiation for cis-UCA production in mouse skin demonstrates that increasing the trans- in vivo. I. Evidence for the existence of a (Gibbs et al., 1993) nor the action spec- UCA content of mouse skin enhances unique photoreceptor in skin and its role in trum for T^T production. Thus, it is likely photocarcinogenesis (Reeve et al., 1989). photoimmunology. J Exp Med 158:84–98 that a complex contribution of both This suggests that, although increased de Fine Olivarius F, Wulf HC, Therkildsen P et al. (1997) Urocanic acid isomers: relation to body chromophores leads to immunosup- UCA may reduce T^T levels, the con- site, pigmentation, stratum corneum thickness pression via a myriad of pathways. These sequent reduction in tumor initiation and photosensitivity. Arch Dermatol Res multifarious effects of UCA on photo­ and T^T-mediated photoimmuno­ 289:501–5 immunosuppression are particularly suppression is not sufficient to counter Fluhr JW, Elias PM, Man M-Q et al. (2010) Is the

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filaggrin–histidine–urocanic acid pathway Protodynamic intracellular acidification by lymphatic vessels (lymphangio­genesis). essential for stratum corneum acidification? cis-urocanic acid promotes apoptosis of The presence of TAMs generally J Invest Dermatol 130:2141–4 melanoma cells in vitro and in vivo. J Invest Dermatol 130:2431–9 correlates with a poor prognosis in most Gibbs NK, Norval M, Traynor NJ et al. (1993) Action human cancers. Importantly, whereas spectra for the trans to cis photoisomerisation Reeve VE, Greenoak GE, Canfield PJ et al. (1989) of urocanic acid in vitro and in mouse skin. Topical urocanic acid enhances UV-induced lymph­angiogenesis observed in many Photochem Photobiol 57:584–90 tumour yield and malignancy in the hairless aggressive cancers correlates with Hemelaar PJ, Beijersbergen van Henegouwen GM mouse. Photochem Photobiol 49:459–64 meta­stasis to regional lymph nodes (1996) Protective effect of N-acetylcysteine Sreevidya CS, Fukunaga A, Khaskhely (e.g., in cutaneous melanoma and in on UVB-induced immunosuppression by et al. (2010) Agents that reverse head/neck and oral squamous cell inhibition of the action of cis-urocanic acid. UV-induced immune suppression and Photochem Photobiol 63:322–7 photocarcinogenesis affect DNA repair. carcinoma (SCC)), the presence and Kaneko K, Smetana-Just U, Matsui M et al. (2008) J Invest Dermatol 130:1428–37 character­ization of prolymphangiogen- cis-Urocanic acid initiates gene transcription Tabachnick J (1957) Urocanic acid, the major acid ic TAMs in cutaneous SCC has not been in primary human keratinocytes. J Immunol soluble, ultraviolet-absorbing compound in previously described. 181:217–24 guinea pig epidermis. Arch Biochem Biophys In this issue, Moussai et al. describe Laihia JK, Kallio JP, Taimen P et al. (2010) 70:295 CD68+/CD163+ TAMs in peritumor- al nonlesional skin (PTNL) of stage I cutaneous SCC as a source of vascu- lar endothelial growth factor (VEGF)-C See related article on pg 229 that correlates with an increase in lym- phatic vessel density (LVD). These data showing lymphangio­genic VEGF-C Lymphangiogenesis Linked produced by a defined subpopulation of TAMs raise a number of interesting to VEGF-C from Tumor-Associated questions about how macrophage-driv- en lymphangiogenesis may promote Macrophages: Accomplices metastasis in SCC. Furthermore, these findings invite investigation of mole- to Metastasis by Cutaneous cules expressed by lymphatic endothe- lial cells (LECs), or at recruitment of Squamous Cell Carcinoma? prolymphangiogenic TAMs, as poten- 1 2 tial therapeutic targets for preventing Martin S. Kluger and Oscar R. Colegio life-threatening metastases to regional During wound healing, dermal macrophages secrete lymphangiogenic draining lymph nodes. vascular endothelial growth factor (VEGF)-C, and lymphatic vessels transport cytokines and cells to draining lymph nodes. In this issue, Moussai et al. Trophic macrophages are recruited show that macrophages in peritumoral nonlesional skin near squamous cell by wounds and tumors carcinoma secrete prolymphangiogenic VEGF-C. Their study suggests how Macrophages are bone marrow–derived tumor-associated macrophages and neolymphatic vessels may coordinate cells that initially circulate as mono- metastasis starting early in cutaneous squamous cell carcinoma. cytes and subsequently differ­entiate Journal of Investigative Dermatology (2011) 131, 17–19. doi:10.1038/jid.2010.347 into tissue-resident macro­phages. Resident macrophages support tissues by phagocytosing apoptotic cells, and they become trophic when activated, Roles for macrophage and the adaptive immune response, and secreting growth, angiogenic, and lymphatic endothelial cells promote healing by tissue remodel­ lymphangiogenic factors needed for near squamous cell carcinoma ing at sites of injury. In contrast, tissue remodeling. Wounding of tis- The primary functions of macrophages tumor-associated macro­phages (TAMs) sues triggers an acute inflammatory were first characterized in settings of are less inflammatory and contribute to response, characterized by the pro- classical inflammation in which they tissue remodeling by promoting the pro- duction of numerous cyto­kines and exert antimicrobial activity, serve as liferation and migration of endothelial chemokines, which recruit and differ- antigen-presenting cells required for cells (ECs) that lead to growth of new entiate additional circulating mono- cytes into macrophages. Wound- associated macrophages have been 1Department of Dermatology and Program in Vascular Biology and Therapeutics, Yale University School proposed to coordinate new tissue 2 of Medicine, New Haven, Connecticut, USA and Department of Dermatology, Yale University School of formation and remodeling. More Medicine, New Haven, Connecticut, USA specifically, macrophages have been Correspondence: Martin S. Kluger, Department of Dermatology, Yale University School of Medicine, Amistad Research Building, 10 Amistad Street, Room 401A, PO Box 208089, New Haven, Connecticut found to regulate vasculogenesis in 06520, USA. E-mail: [email protected] wound healing. Whereas the specific

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