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medications, but not isotretinoin, were associated with an increased risk of hospitalization for IBD. This may reflect closer patient–physician contact among those taking isotretinoin, and thus earlier diagnosis of IBD exacerbation and obviation of the need for hospitalization. This finding does suggest that isotretinoin is safe for use in patients with IBD, though further studies are warranted. Also of interest is that the authors allowed cohort reentry after a 12-month period, as long as patients did not have disqualifying exposures in the previous year. The number of patients accounting for more than one observation is large (54,614 observations among 46,922 unique patients in the isotretinoin group; 239,144 among 184,824 in the topical acne medication group; and 9,533,230 among 1,526,946 in the unexposed group). Although this adds uniformity across all groups, the resulting data are only true if the lag time between isotretinoin and IBD is 1 year or less. For example, a patient treated previously with isotretinoin could constitute an observation in the unexposed cohort, as long as a prescription for isotretinoin had not been given in the previous year. The authors chose this design because the only case–control study revealing an association between IBD and isotretinoin (Crockett et al., 2010) assessed exposure over 12 months before IBD diagnosis. However, although not likely to exceed 1 year, the lag time between isotretinoin exposure and development of IBD is unknown, and Roche has lost lawsuits for exposures occurring more than 12 months prior to the development of IBD (http://www.drugwatch.com/accutane/ lawsuit.php). Therefore, we must interpret the data of Alhusayen et al.’s study cautiously, as it does not hold true if the lag time between isotretinoin and IBD is more than 1 year. The final verdict
Although a final verdict has not been reached, this study adds depth to our understanding of a possible link between isotretinoin and IBD. The findings support the idea that acne itself may contribute to the association observed between isotretinoin and IBD, though this concept requires additional study. Alhusayen et al. raise the idea that any true association between isotretinoin and IBD is likely to be strongest within a younger age group, and that 868
isotretinoin is unlikely to exacerbate IBD. A study directly analyzing a possible association between severe acne and IBD may allow improved understanding of these data. CONFLICT OF INTEREST
The authors state no conflict of interest.
REFERENCES Alhusayen R, Juurlink DN, Muhammad MM et al. (2013) Isotretinoin use and the risk of inflammatory bowel disease: a population based cohort study. J Invest Dermatol 133:907–12 Alikhan A, Henderson GP, Becker L et al. (2011) Acne and inflammatory bowel disease: what is the evidence? J Am Acad Dermatol 65:650–4 Bernstein CN, Nugent Z, Longobardi T et al. (2009) Isotretinoin is not associated with inflammatory bowel disease: a population-based casecontrol study. Am J Gastroenterol 104:2774–8 Brodin MB (1986) Inflammatory bowel disease and isotretinoin. J Am Acad Dermatol 14(5 Pt 1):843 Crockett SD, Gulati A, Sandler RS et al. (2009) A causal association between isotretinoin and
inflammatory bowel disease has yet to be established. Am J Gastroenterol 104:2387–93 Crockett SD, Porter CQ, Martin CF et al. (2010) Isotretinoin use and the risk of inflammatory bowel disease: a case-control study. Am J Gastroenterol 105:1986–93 Margolis DJ, Fanelli M, Hoffstad O et al. (2010) Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. Am J Gastroenterol 105:2610–6 Popescu CM, Popescu R (2011) Isotretinoin therapy and inflammatory bowel disease. Arch Dermatol 147:724–9 Reddy D, Siegel CA, Sands BE et al. (2006) Possible association between isotretinoin and inflammatory bowel disease. Am J Gastroenterol 101:1569–73 Wakabayashi M, Fujimoto N, Uenishi T et al. (2011) A case of acne fulminans in a patient with ulcerative colitis successfully treated with prednisolone and diaminodiphenylsulfone: a literature review of acne fulminans, rosacea fulminans and neutrophilic dermatoses occurring in the setting of inflammatory bowel disease. Dermatology 222:231–5
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Adaptive and Maladaptive Responses in Skin: Mild Heat Exposure Protects against UVB-induced Photoaging in Mice Thomas Haarmann-Stemmann1, Fritz Boege2 and Jean Krutmann1 In this issue, Matsuda et al. demonstrate the protective effect of mild heat preconditioning on UVB-induced photoaging in SKH-1 hairless mice. Mild heat exposure stimulates the upregulation of HSP70 chaperones, which inhibit the activities of matrix-degenerating enzymes, thereby avoiding wrinkle formation. This newly identified heat-mediated process of adaptation to UVB radiation exposure opens new opportunities to slow extrinsic skin aging. Journal of Investigative Dermatology (2013) 133, 868–871. doi:10.1038/jid.2012.435
Induction of adaptive responses by low levels of stress
Low levels of physical, chemical, or biological stress often allow a cell, tissue, or organism to adapt and to improve its resistance to subsequent stress exposure at higher levels (Martins et al., 2011). Such adaptive stress responses are observed in all kingdoms of life and with various types of stressors (radiation,
heavy metals, oxidants, alkylating agents, and heat). They often display a biphasic dose–response pattern, which is typically not addressed by the classical threshold or linear non-threshold models for dose–response relationships, but by alternative mechanisms such as hormesis, desensitization, or preconditioning (Calabrese, 2004; Martins et al., 2011). Prominent examples are
1 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 University, Du¨sseldorf, Germany
Correspondence: Jean Krutmann, IUF—Leibniz Research Institute for Environmental Medicine, Auf’m Hennekamp 50, Du¨sseldorf 40225, Germany. E-mail:
[email protected]
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Clinical Implications
Mild heat pretreatment (42 1C) protects against UVB-driven skin aging, whereas severe heat pretreatment (43 1C and more) induces per se an aging phenotype.
The protective effect of mild heat is because of induction of HSP70, which counteracts UVB-induced matrix-degenerating enzymes and skin inflammation.
Induction of HSP70 by mild heat or other low-dose stressors may thus be a protective option.
the protection against cerebral and cardiac ischemia through hypoxic preconditioning or the extension of lifespan through caloric restriction. Life span is regarded as an especially promising target of preconditioning with agents that interfere with processes that typify extrinsic aging, including the accumulation of damaged macromolecules and increases in molecular heterogeneity (Rattan et al., 2009). Low doses of environmental stressors, long recognized as the environment’s contribution to degenerative aging, may thus be used as preconditioning modalities that decelerate extrinsic aging. One such preconditioning modality is repeated mild heat stress, which exerts beneficial (so-called anti-aging) effects through the induction of chaperones and antioxidant enzymes and stimulation of proteasomal activity and stress kinases (Rattan et al., 2009). In this issue, Matsuda et al. (2013) demonstrate in SKH-1 mice the protective effect of mild heat against UVB radiation-induced skin aging. Mild heat preconditioning induces HSP70 and protects against extrinsic skin aging
As a barrier organ, skin protects an organism, not only against pathogens, but also against physical and chemical stressors. Because of its permanent interaction with the environment, skin undergoes extrinsic aging, with sunlight-induced photoaging as most prominent (Gilchrest and Krutmann, 2006). Besides UV radiation from natural sunlight, tobacco smoke (Morita et al., 2009) and traffic-related particulate matter (Vierkotter et al., 2010) are among the most important environmental factors that initiate and propagate extrinsic skin aging. Chronic
exposure to UV radiation leads to a rarefaction of collagen fibers in the dermis, which presents clinically as coarse wrinkles. This loss of collagen results to a major extent from an extrinsically induced increased expression and activity of the collagen degrading matrix metalloproteinase (MMP)-1 (or its functional murine homolog MMP-13), and a lack of concomitant upregulation of its tissue-specific inhibitor, TIMP-1 (Gilchrest and Krutmann, 2006). MMP-1 is released following exposure to both UVB and UVA radiation, although the primary cellular damage differs. Although UVB rays damage DNA directly through the generation of DNA photoproducts, such as cyclobutane thymidine dimers, UVA radiation damages cellular structures indirectly through the generation of reactive oxygen species (ROS) (Gilchrest and Krutmann, 2006; Krutmann et al., 2012). The dermal release of MMPs is mediated directly through damage to exposed cells as well as through mediators (e.g., cytokines) released by surrounding damaged cells, such as keratinocytes (Fagot et al., 2002). Matsuda et al. (2013) analyzed the effects of preconditioning of mouse skin with heated water at 42 1C for 5 minutes before irradiation in a 10-week chronic UVB exposure protocol. Surprisingly, mild heating of the dorsal skin of SKH-1 mice reduced the hallmarks of UVB-induced photoaging significantly, in particular, loss of skin elasticity, wrinkle formation, and epidermal hyperplasia. In contrast, a 5-minute application of water heated to 43 1C, 44 1C, or 45 1C had the opposite effect, that is, enhanced wrinkle formation and induction of MMP activities, pointing to a typical low dose–induced adaptive effect. These results indicate a typical
biphasic adaptation process: at low doses (preheating to 42 1C), the activity of cutaneous defense mechanisms is enhanced, enabling skin to combat the UVB stress more efficiently, whereas at high doses (preheating to 43 1C and more), the adverse effects of UVB stress are enhanced. Accordingly, Matsuda and colleagues observed the induction of the chaperone HSP70 upon exposure of the skin to mild heat (42 1C). HSP70 family members are typically induced in response to heat stress and to several toxins, especially heavy metals. The family members are important chaperones involved in maintaining proper protein folding and elimination of damaged proteins (Evans et al., 2010). In addition, HSP70 inhibits apoptosis by preventing binding of procaspase-9 to the Apaf-1 apoptosome and exhibits anti-inflammatory properties by repressing NF-kB signaling (Evans et al., 2010). In their study, Matsuda et al. (2013) provide further evidence for a protective function of HSP70 in photoaging by using transgenic mice that overexpress HSP70. Upon chronic UVB exposure, the HSP70 transgene animals exhibit a lesser decrease in skin elasticity and epidermal hyperplasia, which correlates with a decrease in the rate of UVB- and ROSinduced fibroblast apoptosis and a reduced infiltration of the skin by macrophages and neutrophils. The degradation of collagen and elastic fibers in UVB-exposed skin was suppressed in HSP70 transgenic mice in a manner similar to that observed in SKH-1 mice preconditioned with mild heat stress (Figure 1). This protective effect was obviously because of a decreased expression of MMP-2, MMP-9, and elastase, important matrix-degrading enzymes with well-known relevance for skin aging in the applied hairless mouse model (Inomata et al., 2003). Taken together, these findings emphasize the protective effect of HSP70 induction in the skin, especially before extensive UVB exposure, and they open new opportunities for the development of preventive strategies to counteract extrinsic skin aging. Severe heat per se induces aging processes in skin
It is noteworthy that the authors also observed an induction of HSP70 in the dorsal skin of sham-irradiated SKH-1 www.jidonline.org
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UVB Mild heat
-2
MMP
Elastase
-9
MMP
HSP70 HSP70
ECM
Figure 1. Mild heat preconditioning protects against UVB-induced matrix-degenerating enzymes and photoaging. Exposure of SKH-1 hairless mice to mild heat (42 1C) allows the skin to adapt and improves its resistance to chronic UVB irradiation. Mild heat treatment increases the expression of HSP70 chaperone molecules, which subsequently inhibit the activity of MMP-2, MMP-9, and elastase, and thereby maintain the integrity of the extracellular matrix (ECM). MMP, matrix metalloproteinase.
mice treated for 5 minutes with water heated to 43 1C or higher (Matsuda et al., 2012). Under these conditions, MMP-2, MMP-9, elastase, and MMP-13 were upregulated, indicating that severe heat per se induces extrinsic skin aging similar to UVB, as discussed earlier (Cho et al., 2009). Because cutaneous MMP13 activity is increased upon severe heat treatment, but not in response to UVB exposure, heat-induced skin aging is probably mediated predominantly by this collagenase. However, given that HSP70 is induced by mild and severe heating conditions, the question arises why HSP70 is capable of blocking the activity of MMP-2, MMP-9, and elastase, when UVB exposure, but not heat exposure, is the inducing stimulus. Possible explanations for this discrepancy might be the different time-point of HSP70 induction (before or simultaneously with stress exposure), or an activation of the matrix-degenerating enzymes through different (HSP70-sensitive and -insensitive) signaling pathways. These observations feed into an ongoing debate on the contribution of infrared (IR) radiation to sunlightinduced skin aging (Krutmann et al., 2012). IRA radiation is primarily responsible for increased skin temperature, experienced as pleasantly warm to ‘‘burning’’ hot. IR radiation promotes 870
premature skin aging through the upregulation of MMP-1 through a defined retrograde mitochondrial signaling response that is clearly independent of heat generation (Schieke et al., 2002). In contrast, the biological impact of IR radiation in the IRB and IRC spectrum is less well understood (Krutmann et al., 2012), and possibly involves heat generating properties, as demonstrated by a recent study that differentiated the individual effects of natural sunlight, sunlight minus UV radiation, and the heat component within the natural sunlight alone (Cho et al., 2008). Human buttock skin was exposed to sunlight with/without an UV filter (to block UV radiation below 400 nm) or a black cloth, which absorbs IR radiation and generates heat. UV-filtered sunlight significantly increased the MMP-1 expression in exposed skin, indicating that IR radiation contributes to natural sunlight-induced skin responses. Interestingly, increased MMP-1 expression was also observed in skin areas that were covered with a black cloth, indicating that heat exposure alone might exert biological effects on skin as well, and that heat-inducing IRB and IRC rays should perhaps not be regarded as biologically inert (Cho et al., 2008). We have found that exposure of human skin to artificial IRB/IRC radiation did not
Journal of Investigative Dermatology (2013), Volume 133
induce MMP-1 expression in human skin (Krutmann et al., unpublished data), whereas on the other hand, heat is well known to cause erythema ab igne (Hurwitz and Tisserand, 1987), and IRAinduced biological effects may or may not be linked to heating (Schieke et al., 2002; Jantschitsch et al., 2009; Piazena and Kelleher, 2010). Whether IRB/IRC radiation exerts beneficial, preconditioning effects with respect to skin aging may depend on the dose of radiation and the corresponding heat that it generates. Along these lines, low doses may cause mild heating of the skin, followed by HSP70 induction and protection against UV-induced skin aging, whereas higher doses may produce severe heating, thereby activating collagenases and elastases, followed by matrix degradation and wrinkle formation. The study by Matsuda et al. has identified mild heat stress as a promising stimulus to enhance cutaneous adaptation to the deleterious effects caused by UVB radiation, and thus to slow down extrinsic skin aging (Figure 1). Further studies elucidating the precise underlying molecular mechanisms of mild heat preconditioning are clearly necessary before therapeutic options of heat preconditioning can be considered. CONFLICT OF INTEREST
The authors state no conflict of interest.
REFERENCES Calabrese EJ (2004) Hormesis: a revolution in toxicology, risk assessment and medicine. EMBO Rep 5:S37–40 Cho S, Lee MJ, Kim MS et al. (2008) Infrared plus visible light and heat from natural sunlight participate in the expression of MMPs and type I procollagen as well as infiltration of inflammatory cell in human skin in vivo. J Dermatol Sci 50:123–33 Cho S, Shin MH, Kim YK et al. (2009) Effects of infrared radiation and heat on human skin aging in vivo. J Investig Dermatol Symp Proc 14:15–9 Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (hsp70) as an emerging drug target. J Med Chem 53:4585–602 Fagot D, Asselineau D, Bernerd F (2002) Direct role of human dermal fibroblasts and indirect participation of epidermal keratinocytes in MMP-1 production after UV-B irradiation. Arch Dermatol Res 293:576–83 Gilchrest B, Krutmann J (2006) Photoaging of skin. In: Gilchrest B, Krutmann J (eds) Skin Aging. Springer: New York, NY Hurwitz RM, Tisserand ME (1987) Erythema ab igne. Arch Dermatol 123:21–3
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Inomata S, Matsunaga Y, Amano S et al. (2003) Possible involvement of gelatinases in basement membrane damage and wrinkle formation in chronically ultraviolet B-exposed hairless mouse. J Invest Dermatol 120:128–34 Jantschitsch C, Majewski S, Maeda A et al. (2009) Infrared radiation confers resistance to UV-induced apoptosis via reduction of DNA damage and upregulation of antiapoptotic proteins. J Invest Dermatol 129:1271–9 Krutmann J, Morita A, Chung JH (2012) Sun exposure: what molecular photodermatology tells us about its good and bad sides. J Invest Dermatol 132:976–84 Martins I, Galluzzi L, Kroemer G (2011) Hormesis, cell death and aging. Aging (Albany NY) 3:821–8 Matsuda M, Hoshino T, Yamakawa N et al. (2013) Suppression of UV-induced wrinkle formation by induction of HSP70 expression in mice. J Invest Dermatol 133:919–28 Morita A, Torii K, Maeda A et al. (2009) Molecular basis of tobacco smoke-induced premature
skin aging. J Investig Dermatol Symp Proc 14:53–5 Piazena H, Kelleher DK (2010) Effects of infrared-A irradiation on skin: discrepancies in published data highlight the need for an exact consideration of physical and photobiological laws and appropriate experimental settings. Photochem Photobiol 86:687–705 Rattan SI, Fernandes RA, Demirovic D et al. (2009) Heat stress and hormetin-induced hormesis in human cells: effects on aging, wound healing, angiogenesis, and differentiation. Dose Response 7:90–103 Schieke S, Stege H, Kurten V et al. (2002) InfraredA radiation-induced matrix metalloproteinase 1 expression is mediated through extracellular signal-regulated kinase 1/2 activation in human dermal fibroblasts. J Invest Dermatol 119:1323–9 Vierkotter A, Schikowski T, Ranft U et al. (2010) Airborne particle exposure and extrinsic skin aging. J Invest Dermatol 130:2719–26
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CD8 T Cells and IFN-g Emerge as Critical Players for Psoriasis in a Novel Model of Mouse Psoriasiform Skin Inflammation Paola Di Meglio1 and Joa˜o H. Duarte1 A pathogenic crosstalk between epithelial and immune cells underpins the aberrant immune and epidermal responses seen in psoriasis. Data from a novel mouse model of psoriasiform skin inflammation not only highlight the importance of the interplay between keratinocytes, targets of genetic manipulation, and T cells as the major effector cells, but also reveal a critical role for CD8 T cells and IFN-g in disease initiation. Journal of Investigative Dermatology (2013) 133, 871–874. doi:10.1038/jid.2012.426
The complex etiopathogenesis of psoriasis results from the interaction of genetic and environmental factors, leading to dysregulated immune responses that manifest in the skin as prominent epidermal hyperplasia and an inflammatory infiltrate. Although a critical role for T cells is undisputed, it has become increasingly evident that a pathogenic crosstalk between cells of the innate and adaptive immune systems, which also include keratinocytes
(KCs) as ancillary innate immune cells, underpins the aberrant immune and epidermal responses (Di Meglio et al., 2011). Psoriasis susceptibility genes identified thus far fall broadly into three categories—tissue-specific, immunologically innate, and immunologically adaptive (Capon et al., 2012)—further pointing toward critical contributions from both epithelial cells and immune cells in disease initiation.
1
Molecular Immunology, MRC National Institute for Medical Research, London, UK
Correspondence: Paola Di Meglio, Molecular Immunology, National Institute for Medical Research, The Ridgeway, London, NW7 1AA, UK. E-mail:
[email protected]
Contributions of mouse models of psoriasiform skin inflammation to disease understanding
Mouse models of psoriasiform skin inflammation have been used since the early 1990s to elucidate the mechanisms that underlie the human disease (Gudjonsson et al., 2007). For instance, the description of a mouse strain with an intragenic deletion on the sharpin gene affecting homeostatic NF-kB signaling was found to develop skin inflammation spontaneously with some similarities to psoriasis, such as epidermal thickening and intradermal microabscesses. Notably, however, it lacked other important pathological features of human psoriatic lesions, such as epidermal T-cell infiltrates (HogenEsch et al., 1993). The extent to which different mouse models can recapitulate the entire scope of pathological features of psoriasis is a common discussion point—how faithful can a mouse model of psoriasis be, when mouse and human skin have such marked differences at structural and cellular levels? In addition to the genetic differences between the two species, the environmental challenges for mice and humans are quite different, yet still very relevant for disease initiation. By this time, the quest for a system that could satisfactorily model psoriasis was just beginning, and in the past decade a range of transgenic (Gudjonsson et al., 2007) and pharmacological (van der Fits et al., 2009) models have been described, some of which recapitulate the human disease almost completely. As such, genetic manipulation of the signal transducer and activator of transcription 3 (STAT3), NF-kB, and AP-1 pathways in KC has yielded a number of different models with different specificities, but all reproducing the epidermal structural changes and lymphocytic infiltrates common to psoriasis and pointing to the importance of the epithelial cellular compartment in establishing psoriasiform skin inflammation. On the other hand, a different approach to modeling psoriasis using a xenotransplantation model has emphasized the importance of the lymphocytic compartment (Boyman et al., 2004; Conrad et al., 2007). By using human psoriatic skin www.jidonline.org
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