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medications, but not isotretinoin, were isotretinoin is unlikely to exacerbate IBD. inflammatory bowel disease has yet to be associated with an increased risk of A study directly analyzing a possible asso- established. Am J Gastroenterol 104:2387–93 hospitalization for IBD. This may reflect ciation between severe acne and IBD may Crockett SD, Porter CQ, Martin CF et al. (2010) closer patient–physician contact among allow improved understanding of these data. Isotretinoin use and the risk of inflammatory bowel disease: a case-control study. Am J those taking isotretinoin, and thus earlier Gastroenterol 105:1986–93 diagnosis of IBD exacerbation and obvia- CONFLICT OF INTEREST Margolis DJ, Fanelli M, Hoffstad O et al. (2010) tion of the need for hospitalization. This The authors state no conflict of interest. Potential association between the oral tetra- finding does suggest that isotretinoin is cycline class of antimicrobials used to treat REFERENCES acne and inflammatory bowel disease. Am J safe for use in patients with IBD, though Gastroenterol 105:2610–6 further studies are warranted. Alhusayen R, Juurlink DN, Muhammad MM et al. Popescu CM, Popescu R (2011) Isotretinoin (2013) Isotretinoin use and the risk of inflamma- Also of interest is that the authors allowed therapy and inflammatory bowel disease. tory bowel disease: a population based cohort Arch Dermatol 147:724–9 cohort reentry after a 12-month period, as study. J Invest Dermatol 133:907–12 long as patients did not have disqualifying Reddy D, Siegel CA, Sands BE et al. (2006) Alikhan A, Henderson GP, Becker L et al. (2011) Possible association between isotretinoin and exposures in the previous year. The number Acne and inflammatory bowel disease: what is inflammatory bowel disease. Am J Gastro- the evidence? J Am Acad Dermatol 65:650–4 of patients accounting for more than one enterol 101:1569–73 observation is large (54,614 observations Bernstein CN, Nugent Z, Longobardi T et al. (2009) Wakabayashi M, Fujimoto N, Uenishi T et al. Isotretinoin is not associated with inflamma- among 46,922 unique patients in the iso- (2011) A case of acne fulminans in a patient tory bowel disease: a population-based case- with ulcerative colitis successfully treated tretinoin group; 239,144 among 184,824 in control study. Am J Gastroenterol 104:2774–8 the topical acne medication group; and with prednisolone and diaminodiphenyl- Brodin MB (1986) Inflammatory bowel disease and sulfone: a literature review of acne fulminans, 9,533,230 among 1,526,946 in the unex- isotretinoin. J Am Acad Dermatol 14(5 Pt 1):843 rosacea fulminans and neutrophilic derma- posed group). Although this adds uniformity Crockett SD, Gulati A, Sandler RS et al. (2009) A toses occurring in the setting of inflammatory across all groups, the resulting data are only causal association between isotretinoin and bowel disease. Dermatology 222:231–5 true if the lag time between isotretinoin and IBD is 1 year or less. For example, a patient See related article on pg 919 treated previously with isotretinoin could constitute an observation in the unexposed cohort, as long as a prescription for iso- Adaptive and Maladaptive Responses in tretinoin had not been given in the previous year. The authors chose this design because the only case–control study revealing an Skin: Mild Heat Exposure Protects association between IBD and isotretinoin (Crockett et al., 2010) assessed exposure against UVB-induced Photoaging in Mice over 12 months before IBD diagnosis. Thomas Haarmann-Stemmann1, Fritz Boege2 and Jean Krutmann1 However, although not likely to exceed 1 year, the lag time between isotretinoin In this issue, Matsuda et al. demonstrate the protective effect of mild heat exposure and development of IBD is preconditioning on UVB-induced photoaging in SKH-1 hairless mice. Mild heat unknown, and Roche has lost lawsuits exposure stimulates the upregulation of HSP70 chaperones, which inhibit the for exposures occurring more than activities of matrix-degenerating enzymes, thereby avoiding wrinkle formation. 12 months prior to the development of This newly identified heat-mediated process of adaptation to UVB radiation IBD (http://www.drugwatch.com/accutane/ exposure opens new opportunities to slow extrinsic skin aging. lawsuit.php). Therefore, we must interpret Journal of Investigative Dermatology (2013) 133, 868–871. doi:10.1038/jid.2012.435 thedataofAlhusayenet al.’s study cautiously, as it does not hold true if the Induction of adaptive responses by low heavy metals, oxidants, alkylating lag time between isotretinoin and IBD is levels of stress agents, and heat). They often display a more than 1 year. Low levels of physical, chemical, or bio- biphasic dose–response pattern, which logical stress often allow a cell, tissue, is typically not addressed by the classi- The final verdict or organism to adapt and to improve its cal threshold or linear non-threshold Although a final verdict has not been resistance to subsequent stress exposure models for dose–response relationships, reached, this study adds depth to our under- at higher levels (Martins et al., 2011). but by alternative mechanisms such standing of a possible link between isotreti- Such adaptive stress responses are as hormesis, desensitization, or pre- noin and IBD. The findings support the idea observed in all kingdoms of life and conditioning (Calabrese, 2004; Martins that acne itself may contribute to the with various types of stressors (radiation, et al., 2011). Prominent examples are association observed between isotretinoin and IBD, though this concept requires 1 additional study. Alhusayen et al. raise the IUF—Leibniz Research Institute for Environmental Medicine, Auf’m Hennekamp 50, Du¨sseldorf, Germany and 2Institute of Clinical Chemistry and Laboratory Diagnostics, Medical Faculty, Heinrich Heine idea that any true association between University, Du¨sseldorf, Germany isotretinoin and IBD is likely to be strongest Correspondence: Jean Krutmann, IUF—Leibniz Research Institute for Environmental Medicine, Auf’m within a younger age group, and that Hennekamp 50, Du¨sseldorf 40225, Germany. E-mail: [email protected]

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Clinical Implications biphasic adaptation process: at low doses (preheating to 42 1C), the activity Mild heat pretreatment (42 1C) protects against UVB-driven skin aging, of cutaneous defense mechanisms is whereas severe heat pretreatment (43 1C and more) induces per se an enhanced, enabling skin to combat the aging phenotype. UVB stress more efficiently, whereas at The protective effect of mild heat is because of induction of HSP70, which high doses (preheating to 43 1Cand counteracts UVB-induced matrix-degenerating enzymes and skin more), the adverse effects of UVB stress inflammation. are enhanced. Accordingly, Matsuda and colleagues observed the induction Induction of HSP70 by mild heat or other low-dose stressors may thus be a protective option. of the chaperone HSP70 upon exposure oftheskintomildheat(421C). HSP70 family members are typically induced in response to heat stress and to several the protection against cerebral and exposure to UV radiation leads to a toxins, especially heavy metals. The cardiac ischemia through hypoxic rarefaction of collagen fibers in the family members are important chaper- preconditioning or the extension of dermis, which presents clinically as ones involved in maintaining proper pro- lifespan through caloric restriction. Life coarse wrinkles. This loss of collagen tein folding and elimination of damaged span is regarded as an especially pro- results to a major extent from an extrinsi- proteins (Evans et al., 2010). In addition, mising target of preconditioning with cally induced increased expression and HSP70 inhibits apoptosis by preventing agents that interfere with processes activity of the collagen degrading matrix binding of procaspase-9 to the Apaf-1 that typify extrinsic aging, including metalloproteinase (MMP)-1 (or its func- apoptosome and exhibits anti-inflam- the accumulation of damaged macro- tional murine homolog MMP-13), and a matory properties by repressing NF-kB molecules and increases in molecular lack of concomitant upregulation of its signaling (Evans et al., 2010). In their heterogeneity (Rattan et al., 2009). Low tissue-specific inhibitor, TIMP-1 (Gilchrest study, Matsuda et al. (2013) provide doses of environmental stressors, long and Krutmann, 2006). MMP-1 is released further evidence for a protective function recognized as the environment’s contri- following exposure to both UVB and of HSP70 in photoaging by using bution to degenerative aging, may thus UVA radiation, although the primary transgenic mice that overexpress HSP70. be used as preconditioning modalities cellular damage differs. Although UVB Upon chronic UVB exposure, the HSP70 that decelerate extrinsic aging. One rays damage DNA directly through the transgene animals exhibit a lesser such preconditioning modality is repea- generation of DNA photoproducts, such decrease in skin elasticity and epidermal ted mild heat stress, which exerts as cyclobutane thymidine dimers, UVA hyperplasia, which correlates with a beneficial (so-called anti-aging) effects radiation damages cellular structures decrease in the rate of UVB- and ROS- through the induction of chaperones indirectly through the generation of induced fibroblast apoptosis and a redu- and antioxidant enzymes and stimu- reactive oxygen species (ROS) (Gilchrest ced infiltration of the skin by macrophages lation of proteasomal activity and stress and Krutmann, 2006; Krutmann et al., and neutrophils. The degradation of colla- kinases (Rattan et al., 2009). In this 2012). The dermal release of MMPs is gen and elastic fibers in UVB-exposed issue, Matsuda et al. (2013) demon- mediated directly through damage to skin was suppressed in HSP70 transgenic strate in SKH-1 mice the protective exposed cells as well as through medi- mice in a manner similar to that observed effect of mild heat against UVB ators (e.g., cytokines) released by surroun- in SKH-1 mice preconditioned with mild radiation-induced skin aging. ding damaged cells, such as keratinocytes heat stress (Figure 1). This protective effect (Fagot et al., 2002). was obviously because of a decreased Mild heat preconditioning induces HSP70 Matsuda et al. (2013) analyzed the expression of MMP-2, MMP-9, and elas- and protects against extrinsic skin aging effects of preconditioning of mouse skin tase, important matrix-degrading enzymes As a barrier organ, skin protects an with heated water at 42 1Cfor5minutes with well-known relevance for skin aging organism, not only against pathogens, before irradiation in a 10-week chronic in the applied hairless mouse model but also against physical and chemical UVB exposure protocol. Surprisingly, (Inomata et al., 2003). Taken together, stressors. Because of its permanent inter- mild heating of the dorsal skin of these findings emphasize the protective action with the environment, skin SKH-1 mice reduced the hallmarks of effect of HSP70 induction in the skin, undergoes extrinsic aging, with sun- UVB-induced photoaging significantly, especially before extensive UVB expo- light-induced photoaging as most pro- in particular, loss of skin elasticity, sure, and they open new opportunities minent (Gilchrest and Krutmann, 2006). wrinkle formation, and epidermal hy- for the development of preventive strate- Besides UV radiation from natural perplasia. In contrast, a 5-minute appli- gies to counteract extrinsic skin aging. sunlight, tobacco smoke (Morita et al., cation of water heated to 43 1C, 44 1C, 2009) and traffic-related particulate or 45 1C had the opposite effect, that is, Severe heat per se induces aging matter (Vierkotter et al., 2010) are enhanced wrinkle formation and processes in skin among the most important environ- induction of MMP activities, pointing It is noteworthy that the authors also mental factors that initiate and to a typical low dose–induced adaptive observed an induction of HSP70 in the propagate extrinsic skin aging. Chronic effect. These results indicate a typical dorsal skin of sham-irradiated SKH-1

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UVB induce MMP-1 expression in human skin Mild heat (Krutmann et al., unpublished data), whereas on the other hand, heat is well known to cause erythema ab igne (Hurwitz and Tisserand, 1987), and IRA- induced biological effects may or may not be linked to heating (Schieke et al., 2002; Elastase MMP-2 Jantschitsch et al., 2009; Piazena and Kelleher, 2010). Whether IRB/IRC MMP-9 radiation exerts beneficial, precondition- HSP70 ing effects with respect to skin aging may depend on the dose of radiation and the HSP70 corresponding heat that it generates. Along these lines, low doses may cause mild heating of the skin, followed by HSP70 induction and protection against ECM UV-induced skin aging, whereas higher doses may produce severe heating, there- Figure 1. Mild heat preconditioning protects against UVB-induced matrix-degenerating enzymes and by activating collagenases and elastases, photoaging. Exposure of SKH-1 hairless mice to mild heat (42 1C) allows the skin to adapt and improves followed by matrix degradation and wrin- its resistance to chronic UVB irradiation. Mild heat treatment increases the expression of HSP70 chaperone kle formation. The study by Matsuda et al. molecules, which subsequently inhibit the activity of MMP-2, MMP-9, and elastase, and thereby has identified mild heat stress as a maintain the integrity of the extracellular matrix (ECM). MMP, matrix metalloproteinase. promising stimulus to enhance cutane- ous adaptation to the deleterious effects mice treated for 5 minutes with water premature skin aging through the up- caused by UVB radiation, and thus to heated to 43 1C or higher (Matsuda regulation of MMP-1 through a defined slow down extrinsic skin aging (Figure 1). et al., 2012). Under these conditions, retrograde mitochondrial signaling Further studies elucidating the precise MMP-2, MMP-9, elastase, and MMP-13 response that is clearly independent of underlying molecular mechanisms of mild were upregulated, indicating that severe heat generation (Schieke et al., 2002). In heat preconditioning are clearly necessary heat per se induces extrinsic skin aging contrast, the biological impact of IR before therapeutic options of heat precon- similar to UVB, as discussed earlier (Cho radiation in the IRB and IRC spectrum ditioning can be considered. et al., 2009). Because cutaneous MMP- is less well understood (Krutmann et al., 13 activity is increased upon severe heat 2012), and possibly involves heat gene- CONFLICT OF INTEREST treatment, but not in response to UVB rating properties, as demonstrated by The authors state no conflict of interest. exposure, heat-induced skin aging is a recent study that differentiated the probably mediated predominantly by individual effects of natural sunlight, REFERENCES this collagenase. However, given that sunlight minus UV radiation, and the Calabrese EJ (2004) Hormesis: a revolution in HSP70 is induced by mild and severe heat component within the natural sun- toxicology, risk assessment and medicine. EMBO Rep 5:S37–40 heating conditions, the question arises light alone (Cho et al., 2008). Human Cho S, Lee MJ, Kim MS et al. (2008) Infrared plus why HSP70 is capable of blocking the buttock skin was exposed to sunlight visible light and heat from natural sunlight activity of MMP-2, MMP-9, and with/without an UV filter (to block UV participate in the expression of MMPs and elastase, when UVB exposure, but not radiation below 400 nm) or a black type I procollagen as well as infiltration of heat exposure, is the inducing stimulus. cloth, which absorbs IR radiation and inflammatory cell in human skin in vivo. J Dermatol Sci 50:123–33 Possible explanations for this discre- generates heat. UV-filtered sunlight Cho S, Shin MH, Kim YK et al. (2009) Effects of pancy might be the different time-point significantly increased the MMP-1 infrared radiation and heat on human skin of HSP70 induction (before or simul- expression in exposed skin, indicating aging in vivo. J Investig Dermatol Symp Proc taneously with stress exposure), or an acti- that IR radiation contributes to natural 14:15–9 vation of the matrix-degenerating enzymes sunlight-induced skin responses. Interes- Evans CG, Chang L, Gestwicki JE (2010) Heat through different (HSP70-sensitive and tingly, increased MMP-1 expression was shock protein 70 (hsp70) as an emerging drug target. J Med Chem 53:4585–602 -insensitive) signaling pathways. also observed in skin areas that were Fagot D, Asselineau D, Bernerd F (2002) Direct These observations feed into an covered with a black cloth, indicating role of human dermal fibroblasts and indirect ongoing debate on the contribution of that heat exposure alone might exert participation of epidermal keratinocytes in infrared (IR) radiation to sunlight- biological effects on skin as well, and MMP-1 production after UV-B irradiation. induced skin aging (Krutmann et al., that heat-inducing IRB and IRC rays Arch Dermatol Res 293:576–83 2012). IRA radiation is primarily respon- should perhaps not be regarded as Gilchrest B, Krutmann J (2006) Photoaging of skin. In: Gilchrest B, Krutmann J (eds) Skin Aging. sible for increased skin temperature, biologically inert (Cho et al., 2008). Springer: New York, NY experienced as pleasantly warm to We have found that exposure of human Hurwitz RM, Tisserand ME (1987) Erythema ab ‘‘burning’’ hot. IR radiation promotes skin to artificial IRB/IRC radiation did not igne. Arch Dermatol 123:21–3

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Inomata S, Matsunaga Y, Amano S et al. (2003) skin aging. J Investig Dermatol Symp Proc Contributions of mouse models of Possible involvement of gelatinases in base- 14:53–5 psoriasiform skin inflammation to disease ment membrane damage and wrinkle forma- Piazena H, Kelleher DK (2010) Effects of infrared-A understanding tion in chronically ultraviolet B-exposed irradiation on skin: discrepancies in published Mouse models of psoriasiform skin hairless mouse. J Invest Dermatol 120:128–34 data highlight the need for an exact consid- Jantschitsch C, Majewski S, Maeda A et al. (2009) eration of physical and photobiological laws inflammation have been used since Infrared radiation confers resistance to and appropriate experimental settings. Photo- the early 1990s to elucidate the UV-induced apoptosis via reduction of DNA chem Photobiol 86:687–705 mechanisms that underlie the human damage and upregulation of antiapoptotic Rattan SI, Fernandes RA, Demirovic D et al. (2009) disease (Gudjonsson et al., 2007). For proteins. J Invest Dermatol 129:1271–9 Heat stress and hormetin-induced hormesis in instance, the description of a mouse Krutmann J, Morita A, Chung JH (2012) Sun human cells: effects on aging, wound heal- exposure: what molecular photodermatology ing, angiogenesis, and differentiation. Dose strain with an intragenic deletion on tells us about its good and bad sides. J Invest Response 7:90–103 the sharpin gene affecting homeostatic Dermatol 132:976–84 Schieke S, Stege H, Kurten V et al. (2002) Infrared- NF-kB signaling was found to develop Martins I, Galluzzi L, Kroemer G (2011) Hormesis, A radiation-induced matrix metalloproteinase skin inflammation spontaneously with cell death and aging. Aging (Albany NY) 3:821–8 1 expression is mediated through extracellular some similarities to psoriasis, such as signal-regulated kinase 1/2 activation in Matsuda M, Hoshino T, Yamakawa N et al. (2013) epidermal thickening and intradermal Suppression of UV-induced wrinkle formation human dermal fibroblasts. J Invest Dermatol by induction of HSP70 expression in mice. 119:1323–9 microabscesses. Notably, however, it J Invest Dermatol 133:919–28 Vierkotter A, Schikowski T, Ranft U et al. (2010) lacked other important pathological Morita A, Torii K, Maeda A et al. (2009) Molecular Airborne particle exposure and extrinsic skin features of human psoriatic lesions, basis of tobacco smoke-induced premature aging. J Invest Dermatol 130:2719–26 such as epidermal T-cell infiltrates (HogenEsch et al., 1993). The extent to which different mouse models can See related article on pg 955 recapitulate the entire scope of pathological features of psoriasis is a g common discussion point—how faithful CD8 T Cells and IFN- Emerge as can a mouse model of psoriasis be, when mouse and human skin have Critical Players for Psoriasis in a such marked differences at structural and cellular levels? In addition to the Novel Model of Mouse Psoriasiform genetic differences between the two species, the environmental challenges Skin Inflammation for mice and humans are quite different, Paola Di Meglio1 and Joa˜oH.Duarte1 yet still very relevant for disease initiation. By this time, the quest for a A pathogenic crosstalk between epithelial and immune cells underpins the system that could satisfactorily model aberrant immune and epidermal responses seen in psoriasis. Data from a novel psoriasis was just beginning, and in mouse model of psoriasiform skin inflammation not only highlight the importance the past decade a range of transge- of the interplay between keratinocytes, targets of genetic manipulation, and nic (Gudjonsson et al., 2007) and T cells as the major effector cells, but also reveal a critical role for CD8 T cells and pharmacological (van der Fits et al., IFN-g in disease initiation. 2009) models have been descri- bed, some of which recapitulate the Journal of Investigative Dermatology (2013) 133, 871–874. doi:10.1038/jid.2012.426 human disease almost completely. As such, genetic manipulation of the signal transducer and activator of transcription The complex etiopathogenesis of psoriasis (KCs) as ancillary innate immune cells, 3 (STAT3), NF-kB, and AP-1 pathways results from the interaction of genetic and underpins the aberrant immune and epi- in KC has yielded a number of different environmental factors, leading to dysregu- dermal responses (Di Meglio et al., 2011). models with different specificities, but lated immune responses that manifest in Psoriasis susceptibility genes identified all reproducing the epidermal structural the skin as prominent epidermal hyper- thus far fall broadly into three cate- changes and lymphocytic infiltrates plasia and an inflammatory infiltrate. gories—tissue-specific, immunologically common to psoriasis and pointing to Although a critical role for T cells is undis- innate, and immunologically adaptive the importance of the epithelial cellular puted, it has become increasingly evident (Capon et al., 2012)—further pointing compartment in establishing psoriasi- that a pathogenic crosstalk between cells toward critical contributions from both form skin inflammation. On the other of the innate and adaptive immune sys- epithelial cells and immune cells in hand, a different approach to modeling tems, which also include keratinocytes disease initiation. psoriasis using a xenotransplantation model has emphasized the importance 1Molecular Immunology, MRC National Institute for Medical Research, London, UK of the lymphocytic compartment Correspondence: Paola Di Meglio, Molecular Immunology, National Institute for Medical Research, (Boyman et al., 2004; Conrad et al., The Ridgeway, London, NW7 1AA, UK. E-mail: [email protected] 2007). By using human psoriatic skin

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