Editors’ Picks from Experimental Dermatology (January & February 2013)

Correlation between local cortisol metabolism and epidermal hyperproliferative disorders

(a) Immunohistochemical staining of healthy skin and skin tumors with anti-11b-HSD1 and anti-11b-HSD2 antibody. BCC: basal cell carcinoma, SCC: squamous cell carcinoma, SK: seborrhoeic keratosis. Rabbit IgG was used as isotype control. Bar = 100 lm. (b) Quantification of 11b-HSD1 and 11b-HSD2 staining. Bars show the staining index of healthy skin, BCC, SCC and SK. The results are expressed as mean _ SD of 20 normal epidermis samples, 14 BCCs, 18 SCCs and 15 SKs (*P < 0.05 compared with healthy skin).

Recent findings have shown constitutive and regulated production of cortisol by human skin. Cutaneous cortisol can be generated through sequential metabolism of endogenously produced cholesterol or from progesterone that is delivered via the circulation. Thus, the recognized neuroendocrine functions of human skin are extended by a major glucocorticoidogenic capability.

Two key enzymes that regulate local cortisol availability for the glucocorticoid receptor are 11ß-HSD1 and 11ß-HSD2.  11β-HSD1 expresses ketoreductase activity (at a high

NADPH/NADP+ ratio) with the transformation of inactive cortisone into hormonally active cortisol. 11ß-HSD2, in turn, is an NADP+−dependent enzyme that acts exclusively as a dehydrogenase to inactivate cortisol to cortisone. Both of these enzymes are expressed in human skin.

Terao et al. (2013) now report that 11ß-HSD1 decreases in hyperpoliferative disorders like seborrhoeic keratosis and squamous and basal cell carcinoma, while 11ß-HSD2 increases in seborrhoeic keratosis and basal cell carcinoma. Furthermore, treatment of mouse skin with TPA reduces expression of 11ß-HSD1, while forced 11ß-HSD2 overexpression stimulates keratinocyte proliferation.

These important findings offer new insights not only into the potential role of 11ß-HSD1 and 11ß-HSD2 in the development of cutaneous hyperproliferative disorders and perhaps skin carcinogenesis, but also raise the possibility that these enzymes are notable regulators of epidermal homeostasis under physiological conditions. Targeting these enzymes, for example by topically applied small molecules, may therefore represent an exciting novel strategy for the therapeutic manipulation of hyperproliferative human skin disorders.

Selected by A. Slominski, Memphis, TN, USA

Terao M, Itoi S, Murota H, Katayama I. (2013) Expression profiles of cortisol-inactivating enzyme, 11β-hydroxysteroid dehydrogenase-2 in human epidermal tumors and its role in keratinocyte proliferation. Exp Dermatol. 22:98-101. doi:10.1111/exd.12075

 

 

Are NK cells really important in the pathogenesis of psoriasis?

There is considerable evidence suggesting that NK cells play a role in the pathogenesis of psoriasis. In their recent study, Batista et al (2013) specifically looked at the expression of CD57, which is known to be associated with the senescence of NK cells. The investigators found that the frequency of CD7-CD56+CD16+ (NK cell markers) was much higher in involved psoriatic skin. This implies that IFN-g production is higher in the involved area, due to the decreased frequency of CD57+CD56+CD16+ NK senescence cells. Furthermore, their study showed increased expression of NKG2A, a key NK cell activating receptor whose expression correlates well with the level of IFN-g production by NK cells, in involved versus uninvolved psoriatic skin. Therefore, this study further strengthens the concept that NK cells play an important role in the pathogenesis of psoriasis and should, thus, be specifically targeted by future anti-psoriatic therapy.

Selected by A. Gilhar, Haifa, Israel

Batista MD, Ho EL, Kuebler PJ, et al (2013) Skewed distribution of natural killer cells in psoriasis skin lesions. Exp Dermatol 22:64-6. doi:10.1111/exd.12060

 

 

Environmental factors predominately contribute to phenotype variations in XP-C patients

Xeroderma pigmentosum (XP) patients have defects in the nucleotide excision DNA repair pathway. XP complementation group C (XP-C) constitutes one-third of all cases and is therefore the most frequent form of XP. This recessive disorder is characterized by increased sun sensitivity, freckling, pigmentary changes, skin atrophy and UV-induced skin cancer.

To date, there are only four major reports on the genetic background of XP-C. Schäfer et al (2013) now complement these studies by identifying 16 additional German XP-C patients from different ethnic backgrounds. All patients carried homozygous mutations, indicating parental consanguinity. Five mutations are novel, and all of them, except for a single amino acid deletion, lead to premature stop codons and nonsense-mediated mRNA decay. This genetic uniformity may be reflected in the homogeneous phenotypes of the patients.

The authors demonstrated diminished post-UV cell survival and nucleotide excision DNA repair capability of fibroblasts for all patients. Interestingly, they note that one-third of their patients reported sun sensitivity. This particular symptom could not be correlated to a particular mutation or functional outcome. The authors observe that skin cancer occurs mostly in the patients who do not experience sun sensitivity and consequently are less likely to avoid UV exposure. Thus, photosensitivity is a protective factor. Why it affects some patients and not others, even though they have the same mutation, is one of the many mysteries of XP that remains to be solved.

Selected by P.M. Steijlen, Maastricht, the Netherlands

Schäfer A, Hofmann L, Gratchev A, et al (2013) Molecular genetic analysis of 16 XP-C patients from Germany: environmental factors predominately contribute to phenotype variations. Exp Dermatol 22:24–29. doi:10.1111/exd.12052

 

Hair growth control via the mTOR pathway?

The hair follicle continuously undergoes cycles of regeneration coupled with a high proliferation and protein synthesis activity (anagen), followed by an apoptosis-driven organ involution (catagen) and a relative resting phase (telogen). Hair follicle cycling is governed by signaling interactions between specialized, inductive fibroblasts (dermal papilla cells) and hair matrix keratinocytes. Numerous soluble factors, transcription factors, and adhesion molecules play indispensable roles in these signaling interactions.

Kellenberger AJ and Tauchi M (2013) now show that HF cycling is regulated by yet another biologically important molecule, which increasingly attracts interest in several areas of investigative dermatology and has become an important frontier in skin research: mammalian target of rapamycin complex 1 (mTORC1).

The investigators reveal a phase-specific mTORC1 kinase activity: it is high during anagen and low during telogen. Immunohistochemical investigation shows co-expression of an important stem cell marker (keratin 15) in the majority of phophorylated mTOR-positive cells. Moreover, a specific mTORC1 inhibitor, rapamycin, delays spontaneous anagen induction, suggesting that mTORC1 may be involved in the onset of anagen.

These intriguing findings in mice may pave the way for a new treatment of human hair growth disorders, i.e. hirsutism and alopecia, by selectively up- or down-regulating mTORC1 kinase activity.

Selected by M. Nakamura, Kitakyushu, Japan

Kellenberger AJ and Tauchi M (2013) Mammalian target of rapamycin complex 1 (mTORC1) may modulate the timing of anagen entry in mouse hair follicles. Exp Dermatol 22:77-80. doi:10.1111/exd.12062

 

 

PPRE-luciferase mice: A powerful new tool for translational PPAR biology research

Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors that belong to the nuclear hormone receptor family. PPARs were primarily shown to play important roles in lipid and glucose metabolism. There are three PPAR isotypes, PPARα, PPARβ/δ and PPARγ, with distinct tissue expression. All three are expressed in skin, where they regulate various aspects of skin homeostasis. PPARs control keratinocyte proliferation and differentiation, regulate wound healing, and modulate skin inflammation. PPAR activation exerts anti-inflammatory effects in various skin conditions such as irritant and allergic contact dermatitis, atopic dermatitis, and UV-induced erythema.

New experimental tools will accelerate the discovery of novel drugs targeting PPARs. El-Jamal et al. (2013) recently generated new PPAR responsive element-luciferase (PPRE-Luc) mice. These were topically treated with PPARα and PPARγ agonists to determine optimal ligand doses, bioluminescence kinetics, and isoform specific effects. Using these new PPRE-luciferase mice will be useful for screening and characterizing novel PPAR ligands.

Novel compounds optimized in this system will improve our ability to treat many inflammatory skin disorders. It is hoped that these mice will become widely available in the near future to facilitate further in vivo-research into the complex roles of PPARs in skin and to ultimately allow the development of new therapeutic strategies that target these fatty acid-activated transcription factors.

Selected by S. Dubrac, Innsbruck, Austria

El-Jamal N, Dubuquoy L, Auwerx J, et al (2013) In Vivo Imaging Reveals Selective PPAR Activity in the Skin of Peroxisome Proliferator-Activated Receptor Responsive Element-Luciferase Reporter Mice? Exp Dermatol 22:137-40. doi:10.1111/exd.12082

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