Publications by authors named "Jun-ichi Sakabe"

52 Publications

Tp63-expressing adult epithelial stem cells cross lineages boundaries revealing latent hairy skin competence.

Nat Commun 2020 11 6;11(1):5645. Epub 2020 Nov 6.

Laboratory of Stem Cell Dynamics, School of Life Sciences, Ecole Polytechnique Fédérale Lausanne, 1015, Lausanne, Switzerland.

The formation of hair follicles, a landmark of mammals, requires complex mesenchymal-epithelial interactions and it is commonly believed that embryonic epidermal cells are the only cells that can respond to hair follicle morphogenetic signals in vivo. Here, we demonstrate that epithelial stem cells of non-skin origin (e.g. that of cornea, oesophagus, vagina, bladder, prostate) that express the transcription factor Tp63, a master gene for the development of epidermis and its appendages, can respond to skin morphogenetic signals. When exposed to a newborn skin microenvironment, these cells express hair-follicle lineage markers and contribute to hair follicles, sebaceous glands and/or epidermis renewal. Our results demonstrate that lineage restriction is not immutable and support the notion that all Tp63-expressing epithelial stem cells, independently of their embryonic origin, have latent skin competence explaining why aberrant hair follicles or sebaceous glands are sometimes observed in non-skin tissues (e.g. in cornea, vagina or thymus).
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http://dx.doi.org/10.1038/s41467-020-19485-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648065PMC
November 2020

Suprabasin-null mice retain skin barrier function and show high contact hypersensitivity to nickel upon oral nickel loading.

Sci Rep 2020 09 3;10(1):14559. Epub 2020 Sep 3.

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.

Suprabasin (SBSN) is expressed not only in epidermis but also in epithelial cells of the upper digestive tract where metals such as nickel are absorbed. We have recently shown that SBSN level is decreased in the stratum corneum and serum of atopic dermatitis (AD) patients, especially in intrinsic AD, which is characterized by metal allergy. By using SBSN-null (Sbsn) mice, this study was conducted to investigate the outcome of SBSN deficiency in relation to AD. Sbsn mice exhibited skin barrier dysfunction on embryonic day 16.5, but after birth, their barrier function was not perturbed despite the presence of ultrastructural changes in stratum corneum and keratohyalin granules. Sbsn mice showed a comparable ovalbumin-specific skin immune response to wild type (WT) mice and rather lower contact hypersensitivity (CHS) responses to haptens than did WT mice. The blood nickel level after oral feeding of nickel was significantly higher in Sbsn mice than in WT mice, and CHS to nickel was elevated in Sbsn mice under nickel-loading condition. Our study suggests that the completely SBSN deficient mice retain normal barrier function, but harbor abnormal upper digestive tract epithelium that promotes nickel absorption and high CHS to nickel, sharing the features of intrinsic AD.
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http://dx.doi.org/10.1038/s41598-020-71536-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471289PMC
September 2020

Protective role of Galectin-7 for skin barrier impairment in atopic dermatitis.

Clin Exp Allergy 2020 08 14;50(8):922-931. Epub 2020 Jun 14.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Background: Atopic dermatitis (AD) patients have a barrier disorder in association with Th2 dominant skin inflammation. Galectin-7 (Gal-7), a soluble unglycosylated lectin, is highly expressed in the stratum corneum of AD patients. However, the biological significance of increased Gal-7 expression in AD skin lesions remains unclear.

Objective: We aimed to investigate the production mechanism and functional role of Gal-7 in AD patients and IL-4/IL-13-stimulated epidermal keratinocytes.

Methods: We assessed the Gal-7 expression levels in skin lesions and sera from AD patients. Gal-7 levels were also measured in monolayered normal human epidermal keratinocytes (NHEKs) and 3-dimensional (3D)-reconstructed epidermis in the presence or absence of IL-4/IL-13 with or without Stat3, Stat6 or Gal-7 gene silencing.

Results: Gal-7 was highly expressed in the stratum corneum or intercellular space of AD lesional epidermis as assessed by the stratum corneum proteome analysis and immunohistochemistry. A positive correlation was noted between serum Gal-7 level and transepidermal water loss in patients with AD. These clinical findings were corroborated by our in vitro data, which showed that IL-4/IL-13 facilitated the extracellular release of endogenous Gal-7 in both monolayered NHEKs and 3D-reconstructed epidermis. This machinery was caused by IL-4/IL-13-induced cell damage and inhibited by knockdown of Stat6 but not Stat3 in NHEKs. Moreover, we performed Gal-7 knockdown experiment on 3D-reconstructed epidermis and the result suggested that endogenous Gal-7 serves as a protector from IL-4/IL-13-induced disruption of cell-to-cell adhesion and/or cell-to-extracellular matrix adhesion.

Conclusion And Clinical Relevance: Our study unveils the characteristic of Gal-7 and its possible role as an alarmin that reflects the IL-4/IL-13-induced skin barrier impairment in AD.
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http://dx.doi.org/10.1111/cea.13672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496409PMC
August 2020

Potential role of transforming growth factor-beta 1/Smad signaling in secondary lymphedema after cancer surgery.

Cancer Sci 2020 Jul 9;111(7):2620-2634. Epub 2020 Jun 9.

Division of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and skin fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor-beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting fibrosis. Suppression of myofibroblast-dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting skin fibrosis in human secondary lymphedema after cancer surgery.
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http://dx.doi.org/10.1111/cas.14457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385355PMC
July 2020

Plasmacytoid dendritic cells as a possible key player to initiate alopecia areata in the C3H/HeJ mouse.

Allergol Int 2020 Jan 17;69(1):121-131. Epub 2019 Aug 17.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Background: Alopecia areata (AA) is a tissue-specific autoimmune disease, and interferon (IFN)-γ has been regarded as the key cytokine in the pathogenesis of AA. The clinical observation that AA can occur after viral infection or IFN-α administration implies that IFN-α-producing plasmacytoid dendritic cells (pDCs) may be involved in the AA pathogenesis.

Methods: We generated AA in C3H/HeJ mice by intradermal injection of T cells derived from lymph nodes of AA-bearing syngeneic mice and stimulated IL-2, IL-7, and IL-15. Distribution of IFN-γ producing pDCs were immunohistochemically analyzed. Realtime PCR were also demonstrated to detect the expression of IFN-γ mRNA. Hair follicles were cultured with IFN-α in order to calculate the hair elongation. Imiquimod was employed to induce catagen stage. PDCs were injected into C3H/HeJ mice to initiate AA.

Results: In this mouse, IFN-α-producing pDCs densely infiltrated around HFs in not only AA lesional but also vicinity of AA lesion. Importantly, intradermal injection of pDCs induced AA lesions. Finally, IFN-α inhibited hair elongation of murine vibrissae and upregulated MHC class I and CXCL10 levels in vitro.

Conclusions: These findings suggest that IFN-α-producing pDCs initiate AA by inducing apoptosis and increasing Th1/Tc1 chemokine production such as CXCL10, that accumulates Th1/Tc1 cells and result in autoimmune reactions against hair follicles.
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http://dx.doi.org/10.1016/j.alit.2019.07.009DOI Listing
January 2020

Decreased expression of suprabasin induces aberrant differentiation and apoptosis of epidermal keratinocytes: Possible role for atopic dermatitis.

J Dermatol Sci 2019 Sep 27;95(3):107-112. Epub 2019 Jul 27.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Background: Suprabasin (SBSN), a secreted protein, is expressed in various epithelial tissues. The role of SBSN in epidermal differentiation and atopic dermatitis (AD) pathology remains largely unknown.

Objective: To evaluate the effects of SBSN on epidermal keratinocytes and its role in AD.

Methods: We examined the SBSN expression levels in the stratum corneum and the epidermis by proteome analysis and immunohistochemistry, respectively. The serum SBSN concentration was measured by ELISA. These values were compared between AD and healthy control. Morphological changes in the epidermis were investigated in SBSN-knockdown three-dimensional human living skin equivalent (LSE) model with or without IL-4/IL-13.

Results: Epidermal SBSN expression was decreased in AD lesional skin compared to healthy skin, as assessed by the stratum corneum proteome analysis and immunohistochemistry. The SBSN serum levels were significantly lower in AD patients than in normal subjects (P<0.05). The SBSN-deficient LSE exhibited compact stratum corneum, immature stratum granulosum, and increased keratinocyte apoptosis. Th2 cytokines, IL-4 and IL-13, did not affect SBSN expression in LSE. There were no differentiation-associated makers that were affected by the SBSN knockdown. SBSN deficiency-induced apoptosis of keratinocytes was exaggerated by IL-4/IL-13, and accordingly, the addition of recombinant SBSN induced significant keratinocyte proliferation (P<0.05).

Conclusion: Our data demonstrated that SBSN regulates normal epidermal barrier. Th2 cytokines unaffect SBSN expression in keratinocytes, but promote SBSN deficiency-induced apoptosis. It is suggested that SBSN has an anti-apoptotic activity, and its deficiency is involved in the pathogenesis of AD.
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http://dx.doi.org/10.1016/j.jdermsci.2019.07.009DOI Listing
September 2019

Palmar hyperlinearity in early childhood atopic dermatitis is associated with filaggrin mutation and sensitization to egg.

Pediatr Dermatol 2019 Mar 27;36(2):213-218. Epub 2019 Feb 27.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Background/objectives: Palmar hyperlinearity is a typical clinical feature of Filaggrin gene (FLG) null mutations. There are reports of FLG mutations and allergic sensitization; however, reports on the relationship between palmar hyperlinearity to sensitization are limited. This study aimed to examine the association between palmar hyperlinearity and sensitization in atopic dermatitis (AD) children.

Methods: This cross-sectional, case-control study included children ˂ 6 years old with moderate-severe AD whose parents consented for mutation analysis and photographic documentation. Each child underwent genotyping to detect the eight most prevalent FLG mutations in the Japanese population: R501X, 3321delA, S1695X, Q1701X, S2554X, S2889X, S3296X, and K4022X. Clinical features and parameters including egg-specific IgE were examined, and palm photographs were evaluated by 12 trained dermatologists blinded to genotyping results.

Results: Of the 57 patients (age range, 2 months to 5 years; median, 22 months), 16 were heterozygotes and three were compound heterozygotes. Palmar hyperlinearity, as recognized by more than two-thirds of dermatologists, was significantly associated with FLG mutation (P = 0.002, OR = 6.98, 95% CI = 2.1-23.7), and this association was observed especially in children over 2 years. Cross-shaped crease of the thenar eminence, as known in previous reports, also demonstrated significant correlation with FLG mutation. When the children were divided according to the presence or absence of palmar hyperlinearity, the egg white-specific IgE was significantly higher in the hyperlinearity group (55.9 vs 18.3 IU/mL, P < 0.05).

Conclusions: Palmar hyperlinearity indicates possible inherited barrier abnormalities of the skin in early childhood. Its identification may help to predict a more accurate prognosis, such as sensitization.
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http://dx.doi.org/10.1111/pde.13752DOI Listing
March 2019

Clinical course of the first Japanese family with Marie Unna hereditary hypotrichosis: a follow-up report.

Eur J Dermatol 2018 Jun;28(3):406-407

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-1192, Japan.

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http://dx.doi.org/10.1684/ejd.2018.3276DOI Listing
June 2018

Voriconazole-induced photocarcinogenesis is promoted by aryl hydrocarbon receptor-dependent COX-2 upregulation.

Sci Rep 2018 03 22;8(1):5050. Epub 2018 Mar 22.

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.

Voriconazole (VRCZ) induces the development of UV-associated skin cancers. The mechanism underlying the VRCZ-induced carcinogenesis has been largely unknown. Here, we showed that VRCZ metabolites plus UVA generated reactive oxygen species and resultant DNA damage of the epidermis, but did not induce substantial apoptosis in human keratinocytes (KCs). Furthermore, VRCZ per se stimulates aryl hydrocarbon receptor (AhR) and upregulates COX-2, which is a pivotal enzyme for the promotion of UV-associated tumors, in an AhR-ARNT dependent manner of the classical (genomic) pathway. Our findings suggest that the phototoxic moieties of VRCZ metabolites may participate in the initiation phase of VRCZ skin cancer, while VRCZ per se promotes the tumor development. Therefore, during VRCZ therapy, sun exposure protection is essential to prevent photocarcinogenesis caused by VRCZ metabolites plus UV. Chemoprevention with selective COX-2 inhibitors may be helpful to repress the development of skin cancers derived from DNA-damaged KCs.
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http://dx.doi.org/10.1038/s41598-018-23439-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864729PMC
March 2018

Sensitive skin is highly frequent in extrinsic atopic dermatitis and correlates with disease severity markers but not necessarily with skin barrier impairment.

J Dermatol Sci 2018 Jan 2;89(1):33-39. Epub 2017 Nov 2.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Background: Sensitive skin is a condition of cutaneous hypersensitivity to environmental factors. Lactic acid stinging test (LAST) is commonly used to assess sensitive skin and composed of four distinct sensations (pain, burning sensation, itch, and crawly feeling). A link between sensitive skin and barrier dysfunction has been proposed in atopic dermatitis (AD) patients. However, clinical and laboratory factors that are associated with sensitive skin remain unelucidated.

Objective: To investigate relationship between sensitive skin and AD-associated markers.

Methods: Forty-two Japanese AD patients and 10 healthy subjects (HS) were enrolled. AD patients were divided into extrinsic (EAD; high IgE levels) and intrinsic (IAD; normal IgE levels) types. We conducted 1% LAST by assessing the four distinct sensations and calculated the frequencies of sensitive skin in EAD, IAD, and HS. We also performed clinical AD-related tests, including transepidermal water loss (TEWL), visual analogue scale (VAS) of pruritus, and quality of life, and measured laboratory markers, including blood levels of IgE, CCL17/TARC, lactate dehydrogenase (LDH) and eosinophil counts, and concentration levels of serum Th1/Th2 cytokines. Filaggrin (FLG) mutations were examined in 21 patients. These values were subjected to correlation analyses with each of the four sensation elements.

Results: According to the standard criteria for LAST positivity, the frequencies of LAST-positive subjects were 54.8% and 10.0% in AD and HS, respectively (P=0.014). EAD patients showed a significantly (P=0.026) higher frequency of positive LAST (65.6%) than did IAD patients (20.0%). Among the four LAST sensation elements, the crawly feeling and pain scores positively correlated with VAS of pruritus, total serum IgE, mite-specific IgE, CCL17/TARC, and/or LDH. There was no association of the LAST scores with serum Th1/Th2 cytokine levels. Notably, neither TEWL nor FLG mutations correlated with LAST positivity or any sensation scores.

Conclusions: The frequency of sensitive skin is higher in EAD than in IAD. Sensitive skin is associated with AD severity, but not necessarily with barrier condition.
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http://dx.doi.org/10.1016/j.jdermsci.2017.10.011DOI Listing
January 2018

Distinctive downmodulation of plasmacytoid dendritic cell functions by vitamin D3 analogue calcipotriol.

J Dermatol Sci 2016 Oct 3;84(1):71-79. Epub 2016 Jun 3.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Background: In relation to Th17 cell actions, interferon (IFN)-α production by plasmacytoid dendritic cells (pDCs) are involved in the pathogenesis of psoriasis. Vitamin D3 analogues are widely used in the treatment of psoriasis, however, their actions on pDCs are not well understood.

Objective: To investigate the effects of Vitamin D3 analogue calcipotriol (CAL) on pDCs, focusing on the cytokine production and chemotactic activity.

Methods: We compared in mice the effects of CAL, cyclosporine A (CyA), and triamcinolone acetonide (TA) on the cytokine production by pDCs (IFN-α), conventional DCs (TNF-α), and γd T cells (IL-17A). pDCs isolated from mouse spleen cells were stimulated with CpG-ODN in the presence or absence of each drug for 48h. Purified splenic conventional DCs (cDCs) and lymph node γδ T cells were stimulated with CpG-ODN or with anti-CD3/CD28 antibody, respectively. IFN-α, TNF-α and IL-17A in the 48-h culture supernatants were quantified by ELISA. We also studied the ability of CAL to inhibit the chemotaxis of freshly isolated pDCs toward chemerin and VEGF-A, representative chemoattractants of pDCs, by a real-time monitoring method, EZ-Taxiscan. To assess the effect of CAL on pDC accumulation in vivo, we painted CAL ointment to the mouse skin inflamed by topical application of imiquimod cream (IMQ) for 4 consecutive days. In the skin samples, we enumerated 440c pDCs by immunohistochemistry and evaluated the mRNA expression of cytokines by real-time PCR.

Results: CAL significantly inhibited CpG-enhanced pDC IFN-α production at a comparable level to T cell IL-17A production, whereas its effect on cDC TNF-α production was minimal. Accordingly, CAL suppressed the CpG-augmented expression of TLR9 and MyD88. On the contrary, CyA strongly suppressed the production of TNF-α and IL-17A, but not IFN-α. TA inhibited the production of all the cytokines tested. The effect of CAL on the chemotactic activity of pDCs was also evaluated, demonstrating a significant downmodulation by exposure to the reagent. CAL depressed chemerin receptor CMKLR1 expression in pDCs. The in vivo mouse study showed that simultaneous application of CAL to the imiquimod-applied skin reduce both the recruitment of pDCs and the expression of IFN-α2 in the skin.

Conclusions: Our findings suggest that CAL uniquely downmodulates the cytokine production and chemotactic activity of pDCs. The CAL suppression of the in vivo pDC accumulation to the skin suggests that these actions are therapeutically relevant.
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http://dx.doi.org/10.1016/j.jdermsci.2016.06.003DOI Listing
October 2016

Identification and Characterization of a Recessive Missense Mutation p.P277L in SERPINB7 in Nagashima-Type Palmoplantar Keratosis.

J Invest Dermatol 2016 Jan;136(1):325-8

Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1038/JID.2015.347DOI Listing
January 2016

Platelets Regulate the Migration of Keratinocytes via Podoplanin/CLEC-2 Signaling during Cutaneous Wound Healing in Mice.

Am J Pathol 2016 Jan 18;186(1):101-8. Epub 2015 Nov 18.

Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Podoplanin is an endogenous ligand for C-type lectin-like receptor 2 (CLEC-2), which is expressed on platelets. Recent evidence indicates that this specific marker of lymphatic endothelial cells is also expressed by keratinocytes at the edge of wounds. However, whether podoplanin or platelets play a role in keratinocyte activity during wound healing remains unknown. We evaluated the effect of podoplanin expression levels on keratinocyte motility using cultured primary normal human epidermal keratinocytes (NHEKs). Down-regulation of podoplanin in NHEKs via transfection with podoplanin siRNA inhibited their migration, indicating that podoplanin plays a mandatory role in this process. In addition, down-regulation of podoplanin was correlated with up-regulation of E-cadherin, suggesting that podoplanin-mediated stimulation of keratinocyte migration is associated with a loss of E-cadherin. Both the addition of platelets and treatment with CLEC-2 inhibited the migration of NHEKs. The down-regulation of RhoA activity and the up-regulation of E-cadherin in keratinocytes were also induced by CLEC-2. In conclusion, these results suggest that podoplanin/CLEC-2 signaling regulates keratinocyte migration via modulating E-cadherin expression through RhoA signaling. Altering the regulation of keratinocyte migration by podoplanin might be a novel therapeutic approach to improve wound healing.
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http://dx.doi.org/10.1016/j.ajpath.2015.09.007DOI Listing
January 2016

Gross cystic disease fluid protein 15 in stratum corneum is a potential marker of decreased eccrine sweating for atopic dermatitis.

PLoS One 2015 28;10(4):e0125082. Epub 2015 Apr 28.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

It is well known that eccrine sweating is attenuated in patients with atopic dermatitis (AD). We have reported by using proteome analysis that gross cystic disease fluid protein 15 (GCDFP15), a substance secreted from eccrine sweat glands, is decreased in tape-stripped stratum corneum (SC) samples from AD patients. The aim of this study was to evaluate GCDFP15 production by eccrine glands with SC samples and to assess sweating in AD. SC samples were obtained from 51 healthy control (HC) and 51 AD individuals. Sweat samples were from 18 HC and 12 AD subjects. GCDFP15 was quantified by ELISA. By immunohistochemistry, the expression of GCDFP15 in eccrine glands was examined in normal and AD skin specimens. To identify GCDFP15-producing cells, double immunofluorescence staining for GCDFP15 and S100 protein was performed in frozen sections. To address the mechanism underlying the decreased eccrine sweating in AD patients, we examined the expression of cholinergic receptor M3 (CHRM3), a receptor for acetylcholine-induced sweating, in eccrine sweat glands. The amounts of GCDFP15 in the SC extracts were significantly lower in AD than HC (P < 0.0001). The sweat samples from AD patients also had lower levels of GCDFP15 concentration (P < 0.05). Immunohistochemistry showed positive GCDFP15 staining in the eccrine gland secretory cells and the ductal and acrosyringial lumen in normal skin, but AD lacked clear staining. Immunofluorescence staining revealed that GCDFP15 was co-expressed with S100 protein, suggesting that the clear cell of eccrine glands produces GCDFP15. Finally, we found that the expression of CHRM3 was depressed in AD, suggesting contribution to the low sweating. The SC of AD patients contains a low amount of GCDFP15 due to both low sweating and low GCDFP15 concentration in the sweat. GCDFP15 in SC is a potential marker for dysregulated sweating in AD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0125082PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412570PMC
April 2016

Antihistaminic drug olopatadine downmodulates T cell chemotaxis toward CCL17 in patients with atopic dermatitis.

Allergol Int 2015 Apr 2;64(2):200-2. Epub 2015 Jan 2.

Department of Dermatology, Hamamatsu University School of Medicine, Shizuoka, Japan.

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http://dx.doi.org/10.1016/j.alit.2014.10.008DOI Listing
April 2015

Melanocyte-specific cytotoxic T lymphocytes in patients with rhododendrol-induced leukoderma.

J Dermatol Sci 2015 Mar 9;77(3):190-2. Epub 2015 Feb 9.

Department of Dermatology, Hamamatsu University School of Medicine, Japan.

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http://dx.doi.org/10.1016/j.jdermsci.2015.01.017DOI Listing
March 2015

Leukoderma in patients with atopic dermatitis.

J Dermatol 2015 Feb 27;42(2):215-8. Epub 2014 Dec 27.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Atopic dermatitis (AD) is occasionally associated with vitiligo, however, the incidence and conditions of vitiligo or leukoderma, and the characteristics of concurrent AD, remain unclear. We conducted a prospective observational study to investigate the leukoderma-related clinical manifestations and bioparameters of AD. Because vitiligo in AD lesions is occasionally associated with inflammation, we used leukoderma in this study. Enrolled were all AD patients who had been followed up in our AD outpatient clinic and visited within the previous 4 months. During this period, we carefully inspected whether the patients had leukoderma. Eight of 52 patients had leukoderma (15.4%) and were designated as the leukoderma group, and the remaining 44 patients comprised the non-leukoderma group. While the ages were statistically not different between the two groups, female preponderance was significantly observed in the leukoderma group. The leukoderma patients tended to have higher values of SCORAD, CCL17/thymus and activation regulated chemokine and lactate dehydrogenase than the non-leukoderma patients. The leukoderma group was also characterized by a lower frequency of allergic rhinitis and a higher frequency of prurigo lesions. Thus, despite the possession of high AD severity, the leukoderma patients may possibly retain a relatively T-helper 1-skewing state in relation to the development of leukoderma and less association with rhinitis.
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http://dx.doi.org/10.1111/1346-8138.12746DOI Listing
February 2015

A Japanese case of Mal de Meleda with SLURP1 mutation.

J Dermatol 2014 Aug 2;41(8):764-5. Epub 2014 Jul 2.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1111/1346-8138.12539DOI Listing
August 2014

Successful differentiation of herpes zoster-associated erythema multiforme from generalized extension of herpes by rapid polymerase chain reaction analysis.

J Dermatol 2014 Jun;41(6):542-4

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

The polymerase chain reaction (PCR) assay for varicella zoster virus (VZV), herpes simplex virus (HSV)-1 and HSV-2 is available for use. Sometimes the differential diagnosis of the generalized herpes zoster (HZ), HSV1/2, and drug eruption is difficult. We report a case of HZ followed by the vesicular erythema multiforme (EM)-like lesion. In this case the use of PCR was of great assistance. A 78-year-old Japanese man without any significant previous history of disease was admitted to our hospital complaining of zosteriform vesicle on an erythematous base from his right shoulder to the upper arm. We diagnosed him with HZ at the level of right Th2. In spite of the prompt start of antiviral therapy, a secondary new vesiculous erythema developed on his trunk. Clinically, it was quite difficult to differentiate the lesion from the generalized HZ. Rapid PCR assay of effusion and crust for VZV was performed. A PCR assay of VZV was positive for the crust taken from the primary lesion, while it was negative for the effusion and crust of the secondary widespread lesion. We diagnosed the secondary widespread lesion as an EM-type drug eruption induced by acyclovir, or an EM associated with herpes zoster. We then stopped the use of acyclovir and applied steroid ointment of a very strong class for the secondary lesions, which improved after a few days. A PCR assay for VZV was useful for ruling out the generalized HZ in our case with secondary developed vesiculous lesions.
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http://dx.doi.org/10.1111/1346-8138.12479DOI Listing
June 2014

Potential application of in vivo imaging of impaired lymphatic duct to evaluate the severity of pressure ulcer in mouse model.

Sci Rep 2014 Feb 25;4:4173. Epub 2014 Feb 25.

Department of Dermatology, Hamamatsu University School of Medicine, Japan.

Ischemia-reperfusion (IR) injury is a cause of pressure ulcer. However, a mechanism underlying the IR injury-induced lymphatic vessel damage remains unclear. We investigated the alterations of structure and function of lymphatic ducts in a mouse cutaneous IR model. And we suggested a new method for evaluating the severity of pressure ulcer. Immunohistochemistry showed that lymphatic ducts were totally vanished by IR injury, while blood vessels were relatively preserved. The production of harmful reactive oxygen species (ROS) was increased in injured tissue. In vitro study showed a high vulnerability of lymphatic endothelial cells to ROS. Then we evaluated the impaired lymphatic drainage using an in vivo imaging system for intradermally injected indocyanine green (ICG). The dysfunction of ICG drainage positively correlated with the severity of subsequent cutaneous changes. Quantification of the lymphatic duct dysfunction by this imaging system could be a useful strategy to estimate the severity of pressure ulcer.
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http://dx.doi.org/10.1038/srep04173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933905PMC
February 2014

VEGF-A promotes IL-17A-producing γδ T cell accumulation in mouse skin and serves as a chemotactic factor for plasmacytoid dendritic cells.

J Dermatol Sci 2014 May 13;74(2):116-24. Epub 2014 Jan 13.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Background: IL-17-producing CD4(+) T (Th17) cells and their cytokines, IL-17A and IL-22, are deeply involved in the pathogenesis of psoriasis by stimulating epidermal keratinocytes to proliferate and to produce cytokines/chemokines and vascular endothelial growth factor (VEGF)-A. Plasmacytoid dendritic cells (pDCs), infiltrating in psoriatic lesions, are known to exacerbate the Th17-mediated pathogenesis of psoriasis.

Objective: To address the initiative role of VEGF-A in the development of psoriasis and the pDC accumulation.

Methods: Numerical changes and VEGF receptor 1 (VEGFR1) and VEGFR2 expressions were investigated in skin-infiltrating T cells and pDCs of K14-VEGF-A transgenic (Tg) and wild type (WT) mice. The chemotactic properties of VEGF-A for purified splenic pDCs were also evaluated by real-time chemotaxis assay.

Results: By flow cytometry and immunohistochemistry, we observed that the number of dermal IL-17A(+) γδ T cells, but not CD4(+) T cells, was increased in VEGF-A Tg mice, suggesting that the main source of IL-17A was γδ T cells. Moreover, we identified pDCs as 440c(+) cells by immunohistochemistry and as PDCA-1(+)B220(+) cells by flow cytometry, and found that pDCs infiltrated at a higher frequency in VEGF-A Tg than WT mice. pDCs, but not γδ T cells, isolated from the skin expressed VEGFR1 and VEGFR2. Freshly isolated splenic pDCs expressed both receptors after 48-h cultivation. pDCs did not produce cytokines in response to VEGF-A, however, they had a strong velocity of chemotaxis toward VEGF-A at a comparable level to chemerin.

Conclusions: These findings suggest that VEGF-A functions as not only a downstream enhancer but also an upstream initiator by chemoattracting pDCs in psoriatic lesions.
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http://dx.doi.org/10.1016/j.jdermsci.2013.12.013DOI Listing
May 2014

Calcipotriol increases hCAP18 mRNA expression but inhibits extracellular LL37 peptide production in IL-17/IL-22-stimulated normal human epidermal keratinocytes.

Acta Derm Venereol 2014 Sep;94(5):512-6

Department of Dermatology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.

Interleukins (IL)-17A and -22 are involved in the patho-genesis of psoriasis. Cathelicidin LL37 serves as not only antimicrobial peptide but also as autoinflammatory mediator. 1,25-Dihydroxyvitamin D3 analogues, such as calcipotriol, are used as topical treatment for psoriasis. However, the effect of calcipotriol on the mRNA expression/production of human cathelicidin antimicrobial protein (hCAP18) and LL37 peptide by IL-17A/IL-22-stimulated keratinocytes remains controversial. To evaluate the modulatory action of calcipotriol on the production of hCAP18 and LL37, we analysed hCAP18 mRNA expression and hCAP18/LL37 peptide production in IL-17A/IL-22-stimulated cultured human keratinocytes by real-time qPCR, ELISA, western blotting, and immunocytostaining. By western blotting, hCAP18 protein was detected in keratinocytes cultured for 72 h with IL-17/IL-22. Calcipotriol increased hCAP18 mRNA expression in IL-17/IL-22-stimulated keratinocytes. However, LL37 peptide in the culture supernatants was reduced by calcipotriol. Immunostaining revealed that the overproduced LL37 resides within the cells. LL37 promotes psoriasis via interaction with extracellular DNA, but may suppress psoriasis by interfering cytosolic DNA.
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http://dx.doi.org/10.2340/00015555-1775DOI Listing
September 2014

Atopic dermatitis presenting as generalized poikiloderma with filaggrin gene mutation.

J Dermatol 2014 Mar 20;41(3):230-1. Epub 2013 Dec 20.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1111/1346-8138.12339DOI Listing
March 2014

Mutations in SERPINB7, encoding a member of the serine protease inhibitor superfamily, cause Nagashima-type palmoplantar keratosis.

Am J Hum Genet 2013 Nov 24;93(5):945-56. Epub 2013 Oct 24.

Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan; Keio-Maruho Laboratory of Skin Barriology, Keio University School of Medicine, Tokyo 160-8582, Japan; Center for Integrated Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. Electronic address:

"Nagashima-type" palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major causative mutation of c.796C>T (p.Arg266(∗)) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK.
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http://dx.doi.org/10.1016/j.ajhg.2013.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3824127PMC
November 2013

Prostaglandin E₂ is critical for the development of niacin-deficiency-induced photosensitivity via ROS production.

Sci Rep 2013 Oct 17;3:2973. Epub 2013 Oct 17.

1] Department of Dermatology, University of Occupational and Environmental Health, Kitakyushu, Japan [2] Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Pellagra is a photosensitivity syndrome characterized by three "D's": diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.
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http://dx.doi.org/10.1038/srep02973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797990PMC
October 2013

High frequencies of positive nickel/cobalt patch tests and high sweat nickel concentration in patients with intrinsic atopic dermatitis.

J Dermatol Sci 2013 Dec 12;72(3):240-5. Epub 2013 Aug 12.

Department of Dermatology, Hamamatsu University School of Medicine, Japan.

Background: Atopic dermatitis (AD) is classified into extrinsic AD with high serum IgE levels and impaired barrier, and intrinsic AD with low serum IgE levels and unimpaired barrier. Intrinsic AD has a lower frequency of FLG mutations and a higher frequency of circulating Th1 cells, implying that non-protein antigens, represented by metals, may be an exacerbation factor in intrinsic AD.

Objective: To investigate metal allergy in intrinsic AD.

Methods: Enrolled in this study were 86 Japanese AD patients seen in three university hospitals, consisting of 55 extrinsic and 31 intrinsic AD patients. Patch testing was performed, focusing on nickel, cobalt, and chrome, in parallel with other 14 metals. FLG mutations were analyzed in 49 patients (extrinsic, 29; intrinsic, 20). In 17 patients (extrinsic, 12; intrinsic, 5), sweat was collected from the forearms by exercise, and the concentration of nickel was fluorometrically measured.

Results: Nickel, cobalt, and chrome were the major positive metals. Intrinsic AD showed significantly higher percentages of positive reactions than extrinsic AD to nickel (intrinsic 41.9% vs extrinsic 16.4%, P=0.019) and cobalt (38.7% vs 10.9%, P=0.005). There was no significant difference between FLG mutation-bearing and non-bearing patients. The concentration of nickel was higher in the sweat of intrinsic AD than extrinsic AD patients (333.8 vs 89.4ng/g, P=0.0005) and inversely correlated with serum IgE levels.

Conclusions: Nickel and cobalt allergy may be involved in intrinsic AD. Given that the metals are excreted through sweat, intrinsic AD might be exaggerated by highly metal-containing sweat.
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http://dx.doi.org/10.1016/j.jdermsci.2013.07.009DOI Listing
December 2013

Decreased expression of acetylcholine esterase in cholinergic urticaria with hypohidrosis or anhidrosis.

J Invest Dermatol 2014 Jan 7;134(1):276-279. Epub 2013 Jun 7.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu, Japan.

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http://dx.doi.org/10.1038/jid.2013.244DOI Listing
January 2014

D1-like dopamine receptors antagonist inhibits cutaneous immune reactions mediated by Th2 and mast cells.

J Dermatol Sci 2013 Jul 10;71(1):37-44. Epub 2013 Apr 10.

Department of Dermatology, University of Occupational and Environmental Health, Kitakyusyu, Japan.

Background: Dopamine transduces signals via five subtypes of G protein-coupled receptors. Among these subtypes, the D1 and D5 receptors belong to the D1-like group. Although dopamine is known to mediate immune responses, its involvement in cutaneous immunity remains unclear.

Objective: The aim of this study is to determine the role of dopamine and its D1-like receptors in cutaneous immune responses.

Methods: By using the D1-like receptor antagonist SCH 23390, we examined the role of D1-like receptors in murine models of Th1-type contact hypersensitivity and Th2-type atopic dermatitis in vivo, and in mast cells and Th2 cell differentiation in vitro.

Results: Administration of SCH 23390 did not affect Th1-type contact hypersensitivity but suppressed the immediate-type reaction (ITR) and the late phase reaction (LPR) in the atopic dermatitis model. In addition, SCH 23390-treated mice showed higher IFN-γ and lower IL-4 mRNA levels in the ear skin of challenged mice than did non-treated mice as analyzed by real-time RT PCR. Consistently, the passive cutaneous anaphylaxis reaction was significantly reduced in SCH 23390-treated mice. Moreover, dopamine enhanced mast cell degranulation and Th2 cell differentiation, and both activities were abrogated by SCH 23390.

Conclusion: These findings suggest that the D1-like receptors mediate immediate and late phase skin reactions by promoting Th2 induction and mast cell degranulation.
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http://dx.doi.org/10.1016/j.jdermsci.2013.03.008DOI Listing
July 2013
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