Publications by authors named "Gaku Tsuji"

100 Publications

A ubiquitin-like protein encoded by the "noncoding" RNA TINCR promotes keratinocyte proliferation and wound healing.

PLoS Genet 2021 Aug 5;17(8):e1009686. Epub 2021 Aug 5.

Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

Although long noncoding RNAs (lncRNAs) are transcripts that do not encode proteins by definition, some lncRNAs actually contain small open reading frames that are translated. TINCR (terminal differentiation-induced ncRNA) has been recognized as a lncRNA that contributes to keratinocyte differentiation. However, we here show that TINCR encodes a ubiquitin-like protein that is well conserved among species and whose expression was confirmed by the generation of mice harboring a FLAG epitope tag sequence in the endogenous open reading frame as well as by targeted proteomics. Forced expression of this protein promoted cell cycle progression in normal human epidermal keratinocytes, and mice lacking this protein manifested a delay in skin wound healing associated with attenuated cell cycle progression in keratinocytes. We termed this protein TINCR-encoded ubiquitin-like protein (TUBL), and our results reveal a role for TINCR in the regulation of keratinocyte proliferation and skin regeneration that is dependent on TUBL.
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http://dx.doi.org/10.1371/journal.pgen.1009686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341662PMC
August 2021

Daily Fluctuation of Facial Pore Area, Roughness and Redness among Young Japanese Women; Beneficial Effects of Ferment Filtrate Containing Antioxidative Skin Care Formula.

J Clin Med 2021 Jun 5;10(11). Epub 2021 Jun 5.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Young women often complain about the daily fluctuation of their facial skin conditions. However, no objective study has been carried out on such changes. This study is aimed at quantitatively elucidating daily skin fluctuation and evaluating the efficacy of cosmetic skin care treatment. We developed the first portable and self-guided facial skin imaging device (eMR Pro) to reproducibly capture facial images at home. Two 8 week clinical studies were then conducted to analyze daily skin fluctuation of facial pore areas, roughness and redness in young Japanese women ( = 47 in study 1 and = 57 in study 2) by collecting facial images three times a day, during the morning after wake-up, during the morning after face wash, and during the evening after face wash. After a 4 week baseline measurement period (week -4 to week -1), all subjects applied ferment filtrate (GFF, Pitera) skin care formula twice a day for 4 weeks (week 1 to week 4). These three skin conditions did exhibit different fluctuation patterns. The pore area and roughness showed the "morning after wake-up"-largest fluctuation pattern, whereas redness showed the "evening after face wash"-largest fluctuation pattern. GFF treatment significantly reduced the net values and delta fluctuation of pore area, roughness, and redness, which were consistently observed in two studies. In conclusion, the daily fluctuation of facial skin conditions is potentially a new target field for investigating healthy skin maintenance.
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http://dx.doi.org/10.3390/jcm10112502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200969PMC
June 2021

Metalloproteinase 1 downregulation in neurofibromatosis 1: Therapeutic potential of antimalarial hydroxychloroquine and chloroquine.

Cell Death Dis 2021 05 19;12(6):513. Epub 2021 May 19.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Neurofibromatosis type 1 is an autosomal dominant genetic disorder caused by mutation in the neurofibromin 1 (NF1) gene. Its hallmarks are cutaneous findings including neurofibromas, benign peripheral nerve sheath tumors. We analyzed the collagen and matrix metalloproteinase 1 (MMP1) expression in Neurofibromatosis 1 cutaneous neurofibroma and found excessive expression of collagen and reduced expression of MMP1. To identify new therapeutic drugs for neurofibroma, we analyzed phosphorylation of components of the Ras pathway, which underlies NF1 regulation, and applied treatments to block this pathway (PD184352, U0126, and rapamycin) and lysosomal processes (chloroquine (CQ), hydroxychloroquine (HCQ), and bafilomycin A (BafA)) in cultured Neurofibromatosis 1 fibroblasts. We found that downregulation of the MMP1 protein was a key abnormal feature in the neurofibromatosis 1 fibroblasts and that the decreased MMP1 was restored by the lysosomal blockers CQ and HCQ, but not by the blockers of the Ras pathway. Moreover, the MMP1-upregulating activity of those lysosomal blockers was dependent on aryl hydrocarbon receptor (AHR) activation and ERK phosphorylation. Our findings suggest that lysosomal blockers are potential candidates for the treatment of Neurofibromatosis 1 neurofibroma.
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http://dx.doi.org/10.1038/s41419-021-03802-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134427PMC
May 2021

Aryl Hydrocarbon Receptor and Dioxin-Related Health Hazards-Lessons from Yusho.

Int J Mol Sci 2021 Jan 12;22(2). Epub 2021 Jan 12.

Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan.

Poisoning by high concentrations of dioxin and its related compounds manifests variable toxic symptoms such as general malaise, chloracne, hyperpigmentation, sputum and cough, paresthesia or numbness of the extremities, hypertriglyceridemia, perinatal abnormalities, and elevated risks of cancer-related mortality. Such health hazards are observed in patients with Yusho (oil disease in Japanese) who had consumed rice bran oil highly contaminated with 2,3,4,7,8-pentachlorodibenzofuran, polychlorinated biphenyls, and polychlorinated quaterphenyls in 1968. The blood concentrations of these congeners in patients with Yusho remain extremely elevated 50 years after onset. Dioxins exert their toxicity via aryl hydrocarbon receptor (AHR) through the generation of reactive oxygen species (ROS). In this review article, we discuss the pathogenic implication of AHR in dioxin-induced health hazards. We also mention the potential therapeutic use of herbal drugs targeting AHR and ROS in patients with Yusho.
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http://dx.doi.org/10.3390/ijms22020708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828254PMC
January 2021

IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, an Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis.

Int J Mol Sci 2020 Dec 10;21(24). Epub 2020 Dec 10.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan.

Skin barrier dysfunction, including reduced filaggrin (FLG) and loricrin (LOR) expression, plays a critical role in atopic dermatitis (AD) development. Since aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, mediates keratinocyte differentiation, it is a potential target for AD treatment. Recently, clinical studies have shown that tapinarof, an AHR modulator, attenuated the development of AD. To examine the molecular mechanism involved in this, we analyzed tapinarof-treated normal human epidermal keratinocytes (NHEKs). Tapinarof upregulated FLG and LOR mRNA and protein expression in an AHR-dependent manner. Tapinarof also induced the secretion of IL-24, a cytokine that activates Janus kinase (JAK)-signal transducer and activator of transcription (STAT), leading to the downregulation of FLG and LOR expression. Knockdown of either IL-24 or STAT3 expression by small interfering RNA (siRNA) transfection augmented the upregulation of FLG and LOR expression induced by tapinarof, suggesting that inhibition of the IL-24/STAT3 axis during AHR activation supports the improvement of skin barrier dysfunction. Furthermore, tapinarof alone could restore the downregulation of FLG and LOR expression induced by IL-4, a key cytokine of AD, and its combination with JAK inhibitors enhanced this effect. These findings provide a new strategy for treating AD using AHR modulators and JAK inhibitors.
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http://dx.doi.org/10.3390/ijms21249412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764126PMC
December 2020

Cancer- and noncancer-specific cumulative incidence of death after exposure to polychlorinated biphenyls and dioxins: A competing risk analysis among Yusho patients.

Environ Int 2021 02 13;147:106320. Epub 2020 Dec 13.

Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, Japan; Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: In competing risks settings, the cause-specific cumulative incidence function is of great interest since it quantifies cumulative risk in the presence of other causes. To date, however, long-term cancer- and noncancer-specific mortality in Yusho patients exposed to polychlorinated biphenyls (PCBs) and dioxin-related compounds has not been estimated.

Methods: We identified vital status and cause of death for Yusho patients between 1968 and 2017. Risk of cancer- and noncancer-specific mortality was estimated using a flexible hazards-based regression model, with accounting for competing events.

Results: In total, 1664 Yusho patients with 63,566 person-years of follow-up were included in the analysis. 50-year cumulative incidence of cancer mortality was 12.4% (95% confidence interval [CI], 10.5-14.7) in males and 4.7% (95% CI, 3.5-6.4) in females (difference, 7.7 percentage points [95% CI, 5.2-10.2]; adjusted hazard ratio for males, 2.61 [95% CI, 1.93-3.52]). For noncancer, the 50-year cumulative incidence of mortality was 35.4% (95% CI, 32.8-38.3) in males and 35.6% (95% CI, 33.3-38.1) in females (difference, -0.2 percentage points [95% CI, -3.5 to 3.1]; adjusted hazard ratio for males, 1.51 [95% CI, 1.26-1.82]).

Conclusions: These findings confirm that male Yusho patients have a significantly higher risk of cumulative incidence of cancer-specific mortality than female Yusho patients. Our findings might be useful in providing Yusho patients with more accurate information on cancer prognosis and survivorship and help determine more appropriate disease management.
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http://dx.doi.org/10.1016/j.envint.2020.106320DOI Listing
February 2021

Mortality in Yusho patients exposed to polychlorinated biphenyls and polychlorinated dibenzofurans: a 50-year retrospective cohort study.

Environ Health 2020 11 23;19(1):119. Epub 2020 Nov 23.

Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, Japan.

Background: In 1968, the Yusho incident resulted in accidental exposure to polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and related compounds in Japan. This study updated the risk of mortality in Yusho patients.

Methods: We obtained updated cohort data for all Yusho patients for the period 1968-2017. We calculated standardized mortality ratios (SMRs) for all-cause and cause-specific mortality over a 50-year follow-up period compared with the general population in Japan.

Results: A total of 1664 Yusho patients with 63,566 person-years of follow up were included in the analysis. Among males, excess mortality was observed for all cancers (SMR: 1.22, 95% confidence interval [CI]: 1.02 to 1.45) and lung cancer (SMR: 1.59, 95% CI: 1.12 to 2.19). Among females, increased mortality was observed for liver cancer (SMR: 2.05, 95% CI: 1.02 to 3.67). No significant increase was seen in non-cancer-related mortality compared with the general population.

Conclusions: Carcinogenic risk in humans after exposure to PCBs and PCDFs remains higher among Yusho patients. Our findings suggest the importance of care engagement and optimum management to deal with the burden of Yusho disease.
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http://dx.doi.org/10.1186/s12940-020-00680-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685647PMC
November 2020

Basics and recent advances in the pathophysiology of atopic dermatitis.

J Dermatol 2021 Feb 29;48(2):130-139. Epub 2020 Oct 29.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Atopic dermatitis is a common, chronic inflammatory skin disease that is characterized by skin barrier dysfunction, inflammation and intense itch. Although the exact mechanisms behind its pathogenesis remain unclear, it is evident that the complex interplay among barrier dysfunction, inflammation and itch are critical in its development, progression and chronicity. Abnormalities in filaggrin, intercellular lipids and tight junctions induce barrier-disrupted skin, which produces thymic stromal lymphopoietin, interleukin (IL)-25 and IL-33; these in turn promote skin inflammation characterized by type 2 immune deviation. This inflammation then downregulates the expression of filaggrin in keratinocytes and exacerbates epidermal barrier dysfunction. Furthermore, various itch mediators/pruritogens produced during this inflammatory process can act directly on sensory nerves and cause itch. In this review, we summarize the basics and recent advances in our understanding of the pathophysiology of atopic dermatitis focusing on three aspects: barrier dysfunction, skin inflammation and itch.
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http://dx.doi.org/10.1111/1346-8138.15664DOI Listing
February 2021

Guidelines for the management of dermatomycosis (2019).

J Dermatol 2020 Dec 25;47(12):1343-1373. Epub 2020 Sep 25.

Maruyama Dermatology Clinic, Tokyo, Japan.

The "Guidelines for the management of dermatomycosis" of the Japanese Dermatological Association were first published in Japanese in 2009 and the Guidelines Committee of the Japanese Dermatological Association revised it in 2019. The first guidelines was prepared according to the opinions of the Guidelines Committee members and it was of educational value. The revised version is composed of introductory descriptions of the disease concepts, diagnosis, medical mycology and recent advances in treatment, along with clinical questions (CQ), which is intended to help in general practice for dermatologists. The CQ are limited to those involved in therapy but include some of the recently launched antifungal agents. The level of evidence and the degree of recommendation for each item were reviewed by the committee based on clinical studies published by 2018. For rare dermatomycoses, recommendations by the committee are described in the guidelines. In this field, there are still few good quality studies on treatment. Periodic revision in line with new evidence is necessary.
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http://dx.doi.org/10.1111/1346-8138.15618DOI Listing
December 2020

Scratch wound-induced CXCL8 upregulation is EGFR-dependent in keratinocytes.

J Dermatol Sci 2020 Sep 15;99(3):209-212. Epub 2020 Jul 15.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Research and Clinical Center for Yusho and Dioxin, Kyushu University, Fukuoka, Japan; Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jdermsci.2020.07.002DOI Listing
September 2020

Pathogenic implication of epidermal scratch injury in psoriasis and atopic dermatitis.

J Dermatol 2020 Sep 16;47(9):979-988. Epub 2020 Jul 16.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Mechanical scratching, a common external stress affecting the skin, is induced by various causes, such as pruritus. Scratch injury to epidermal keratinocytes upregulates the production and release of chemokine (C-C motif) ligand 20 (CCL20) in vitro, which selectively chemoattracts interleukin (IL)-17A-producing immune cells that express chemokine (C-C motif) receptor 6 (CCR6). In IL-17A-dominant psoriasis, scratch-induced CCL20 upregulation and subsequent accumulation of IL-17A-producing immune cells and CCR6 mature dendritic cells may trigger the development of psoriatic lesions, a process known as the Koebner phenomenon. In IL-4/IL-13-dominant atopic dermatitis, pruritus and subsequent scratching are the primary symptoms. Scratch-induced CCL20 production from keratinocytes may explain why IL-17A levels are also elevated in atopic dermatitis. In contrast, mechanical scratching is likely to negatively regulate IL-13 signaling by upregulating the expression of IL-13 receptor α2, which serves as a decoy receptor for IL-13 in keratinocytes. In this review, we summarize current reports on topics related to the pathogenic role of epidermal scratch injury in psoriasis and atopic dermatitis.
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http://dx.doi.org/10.1111/1346-8138.15507DOI Listing
September 2020

Inhibition of mite-induced dermatitis, pruritus, and nerve sprouting in mice by the endothelin receptor antagonist bosentan.

Allergy 2021 01 16;76(1):291-301. Epub 2020 Jul 16.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Endothelin-1 (EDN1) can evoke histamine-independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL-25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model.

Methods: We analyzed the mite-induced AD-like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3 weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation.

Results: Topical application of bosentan significantly attenuated the development of mite-induced AD-like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation-regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13, Il17, and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose- and time-dependent manner, bosentan treatment attenuated this.

Conclusions: EDN1 plays a significant role in mite-induced inflammation and itch. Topical bosentan is a potential protective candidate for AD.
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http://dx.doi.org/10.1111/all.14451DOI Listing
January 2021

Topical application of endothelin receptor a antagonist attenuates imiquimod-induced psoriasiform skin inflammation.

Sci Rep 2020 06 11;10(1):9510. Epub 2020 Jun 11.

Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Endothelin-1 (ET-1) is well known as the most potent vasoconstrictor, and can evoke histamine-independent pruritus. Recently, its involvement in cutaneous inflammation has begun to draw attention. The upregulation of ET-1 expression in the epidermis of human psoriasis patients has been reported. It was also demonstrated that ET-1 can stimulate dendritic cells to induce Th17/1 immune responses. However, the role of the interaction between ET-1 and ET-1 receptors in the pathogenesis of psoriasis remains elusive. Here, we investigated the effects of ET-1 receptor antagonist on imiquimod (IMQ) -induced psoriasiform dermatitis in mouse. Psoriasis-related cytokines such as IL-17A and TNF-α induced ET-1 expression in human keratinocytes. Topical application of selective endothelin A receptor (ETAR) antagonist ambrisentan significantly attenuated the development of IMQ-induced psoriasiform dermatitis and also significantly inhibited the histological inflammation and cytokine expression (TNF-α, IL-12p40, IL-12 p19, and IL-17) in the lesional skin of the mouse model. Furthermore, topical application of ambrisentan suppressed phenotypic and functional activation of dendritic cells in lymph nodes. Our findings indicate that the ET-1 and ETAR axis plays an important role in the pathogenesis of psoriasis and is a potential therapeutic target for treating psoriasis.
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http://dx.doi.org/10.1038/s41598-020-66490-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289852PMC
June 2020

Baicalein Inhibits Benzo[a]pyrene-Induced Toxic Response by Downregulating Src Phosphorylation and by Upregulating NRF2-HMOX1 System.

Antioxidants (Basel) 2020 Jun 9;9(6). Epub 2020 Jun 9.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Benzo[a]pyrene (BaP), a major environmental pollutant, activates aryl hydrocarbon receptor (AHR), induces its cytoplasmic-to-nuclear translocation and upregulates the production of cytochrome P450 1A1 (CYP1A1), a xenobiotic metabolizing enzyme which metabolize BaP. The BaP-AHR-CYP1A1 axis generates reactive oxygen species (ROS) and induces proinflammatory cytokines. Although the anti-inflammatory phytochemical baicalein (BAI) is known to inhibit the BaP-AHR-mediated CYP1A1 expression, its subcellular signaling remains elusive. In this study, normal human epidermal keratinocytes and HaCaT keratinocytes were treated with BAI, BaP, or BAI + BaP, and assessed for the CYP1A1 expression, antioxidative pathways, ROS generation, and proinflammatory cytokine expressions. BAI and BAI-containing herbal medicine Wogon and Oren-gedoku-to could inhibit the BaP-induced CYP1A1 expression. In addition, BAI activated antioxidative system nuclear factor-erythroid 2-related factor-2 (NRF2) and heme oxygenase 1 (HMOX1), leading the reduction of BaP-induced ROS production. The BaP-induced IL1A and IL1B was also downregulated by BAI. BAI inhibited the phosphorylation of Src, a component of AHR cytoplasmic complex, which eventually interfered with the cytoplasmic-to-nuclear translocation of AHR. These results indicate that BAI and BAI-containing herbal drugs may be useful for inhibiting the toxic effects of BaP via dual AHR-CYP1A1-inhibiting and NRF2-HMOX1-activating activities.
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http://dx.doi.org/10.3390/antiox9060507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346154PMC
June 2020

Selective PPARα agonist pemafibrate inhibits TNF-α-induced S100A7 upregulation in keratinocytes.

J Dermatol Sci 2020 Jul 19;99(1):69-72. Epub 2020 May 19.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, Japan; Division of Skin Surface Sensing, Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jdermsci.2020.05.005DOI Listing
July 2020

Acrosyringeal endothelin-1 expression: Potential for fostering melanocytes in volar sites.

J Dermatol 2020 Aug 18;47(8):924-925. Epub 2020 May 18.

Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1111/1346-8138.15404DOI Listing
August 2020

Aryl Hydrocarbon Receptor Activation Downregulates IL-33 Expression in Keratinocytes via Ovo-Like 1.

J Clin Med 2020 Mar 24;9(3). Epub 2020 Mar 24.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Background: IL-33, one of the IL-1 superfamily cytokines, has been shown to be associated with pruritus and inflammation in atopic dermatitis (AD). Furthermore, IL-33 production derived from keratinocytes reportedly has a crucial role in the development of AD; however, the mechanism of IL-33 expression has not been fully understood.

Methods: We analyzed IL-33 expression in normal human epidermal keratinocytes (NHEKs) treated with IL-4.

Results: IL-4 induced the upregulation of IL-33 expression in NHEKs. Based on the findings 1) that ovo-like 1 (OVOL1), a susceptible gene of AD, upregulates filaggrin (FLG) and loricrin (LOR) expression in NHEKs and 2) that reduced expression of FLG and LOR leads to production of IL-1 superfamily cytokines, we examined the involvement of OVOL1 in IL-33 expression in NHEKs. Knockdown of OVOL1 induced upregulation of IL-33 expression. Moreover, because Glyteer, an activator of aryl hydrocarbon receptor (AHR), reportedly upregulates OVOL1 expression, we examined whether treatment with Glyteer inhibited IL-33 expression in NHEKs. Treatment with Glyteer inhibited IL-4-induced upregulation of IL-33 expression, which was canceled by knockdown of either AHR or OVOL1.

Conclusions: Activation of the AHR-OVOL1 axis inhibits IL-4-induced IL-33 expression, which could be beneficial for the treatment of AD.
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http://dx.doi.org/10.3390/jcm9030891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141508PMC
March 2020

Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis.

Cell Death Discov 2020 4;6:11. Epub 2020 Mar 4.

2Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan.

Psoriasis is a systemic inflammatory disease significantly associated with comorbidities including type 2 diabetes mellitus (T2DM). Metformin is utilized as a first-line agent for treating T2DM. Although metformin reportedly inhibits mature IL-1β secretion via NLRP3 inflammasome in macrophages of T2DM patients, it remains unclear whether it affects skin inflammation in psoriasis. To test this, we analysed normal human epidermal keratinocytes (NHEKs), a major skin component, stimulated with the key mediators of psoriasis development, TNF-α and IL-17A. This stimulation induced the upregulation of pro-IL-1β mRNA and protein levels, and subsequently mature IL-1β secretion, which was inhibited by metformin treatment. To further reveal the mechanism involved, we examined how metformin treatment affected NLRP3 inflammasome activated by TNF-α and IL-17A stimulation. We found that this treatment downregulated caspase-1 expression, a key mediator of NLRP3 inflammasome. Furthermore, inhibitors of AMPK and SIRT1 abrogated the downregulation of caspase-1 induced by metformin treatment, indicating that AMPK and SIRT1 are essential for the inhibitory effect on NLRP3 inflammasome in NHEKs. As IL-1β stimulation induced upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels in NHEKs, we examined whether metformin treatment affects such gene expression. Metformin treatment inhibited upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels induced by TNF-α and IL-17A stimulation. Finally, we examined whether metformin administration affected psoriasis development in an imiquimod-induced mouse psoriasis model. Oral metformin treatment significantly decreased ear thickness, epidermal hyperplasia and inflammatory cell infiltration. A cytokine profile in the epidermis under metformin treatment showed that IL-1β, Cxcl1, Cxcl2, S100a7, S100a8 and S100A9 mRNA levels were downregulated compared with control levels. These results indicate that metformin administration prevented psoriasis development in vivo. Collectively, our findings suggest that metformin-mediated anti-psoriatic effects on the skin have the potential for treating psoriasis in T2DM patients.
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http://dx.doi.org/10.1038/s41420-020-0245-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055596PMC
March 2020

Interleukin-17A and Keratinocytes in Psoriasis.

Int J Mol Sci 2020 Feb 13;21(4). Epub 2020 Feb 13.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan.

The excellent clinical efficacy of anti-interleukin 17A (IL-17A) biologics on psoriasis indicates a crucial pathogenic role of IL-17A in this autoinflammatory skin disease. IL-17A accelerates the proliferation of epidermal keratinocytes. Keratinocytes produce a myriad of antimicrobial peptides and chemokines, such as CXCL1, CXCL2, CXCL8, and CCL20. Antimicrobial peptides enhance skin inflammation. IL-17A is capable of upregulating the production of these chemokines and antimicrobial peptides in keratinocytes. CXCL1, CXCL2, and CXCL8 recruit neutrophils and CCL20 chemoattracts IL-17A-producing CCR6 immune cells, which further contributes to forming an IL-17A-rich milieu. This feed-forward pathogenic process results in characteristic histopathological features, such as epidermal hyperproliferation, intraepidermal neutrophilic microabscess, and dermal CCR6 cell infiltration. In this review, we focus on IL-17A and keratinocyte interaction regarding psoriasis pathogenesis.
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http://dx.doi.org/10.3390/ijms21041275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072868PMC
February 2020

Implications of IL-13Rα2 in atopic skin inflammation.

Allergol Int 2020 Jul 6;69(3):412-416. Epub 2020 Feb 6.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Atopic dermatitis (AD) is a common eczematous skin disorder characterized by skin inflammation, barrier disruption, chronic pruritus and marked scratching. Th2 cytokines, especially IL-13, play a pathogenic role in AD. IL-13 signals via a heterodimeric receptor composed of IL-4Rα and IL-13 Rα1. A second receptor, IL-13 Rα2, binds to IL-13 with high affinity, but it works as a decoy receptor. IL-13 Rα2 is overexpressed in the lesional skin of AD. Notably, mechanical scratching, as well as IL-13 itself, also upregulates IL-13 Rα2 expression. The scratch-induced IL-13 Rα2 upregulation may attenuate the IL-13-mediated epidermal barrier dysfunction and dermal fibrosis. Recent studies stress an importance of another IL-13 Rα2 ligand, chitinase 3-like 1 or YKL-40 in Th2 differentiation. However, the implications of increased IL-13 Rα2 levels remain elusive in AD. In this review, we summarize the recent topics on IL-13 Rα2 in atopic skin inflammation.
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http://dx.doi.org/10.1016/j.alit.2020.01.005DOI Listing
July 2020

The EGFR-ERK/JNK-CCL20 Pathway in Scratched Keratinocytes May Underpin Koebnerization in Psoriasis Patients.

Int J Mol Sci 2020 Jan 9;21(2). Epub 2020 Jan 9.

Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582, Japan.

Epidermal keratinocytes represent a rich source of C-C motif chemokine 20 (CCL20) and recruit CCR6 interleukin (IL)-17A-producing T cells that are known to be pathogenic for psoriasis. A previous study revealed that scratch injury on keratinocytes upregulates CCL20 production, which is implicated in the Koebner phenomenon characteristically seen in psoriasis patients. However, the molecular mechanisms leading to scratch-induced CCL20 production remain elusive. In this study, we demonstrate that scratch injury upregulates the phosphorylation of epidermal growth factor receptor (EGFR) and that the specific EGFR inhibitor PD153035 attenuates scratch-induced CCL20 upregulation in an extracellular signal-related kinase (ERK)-dependent, and to a lesser extent, a c-Jun N-terminal kinase (JNK)-dependent but p38 mitogen-activated protein kinase (MAPK)-independent manner. Immunoreactive CCL20 was visualized in the keratinocytes that lined the scratched wound. IL-17A also induced the phosphorylation of EGFR and further augmented scratch-induced CCL20 upregulation. The EGFR-ERK/JNK-CCL20 pathway in scratched keratinocytes may explain why Koebnerization is frequently seen in psoriasis patients.
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http://dx.doi.org/10.3390/ijms21020434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013594PMC
January 2020

Chloracne and Hyperpigmentation Caused by Exposure to Hazardous Aryl Hydrocarbon Receptor Ligands.

Int J Environ Res Public Health 2019 12 3;16(23). Epub 2019 Dec 3.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan.

Dioxins and dioxin-like compounds are environmental pollutants that are hazardous to human skin. They can be present in contaminated soil, water, and air particles (such as ambient PM). Exposure to a high concentration of dioxins induces chloracne and hyperpigmentation. These chemicals exert their toxic effects by activating the aryl hydrocarbon receptor (AHR) which is abundantly expressed in skin cells, such as keratinocytes, sebocytes, and melanocytes. Ligation of AHR by dioxins induces exaggerated acceleration of epidermal terminal differentiation (keratinization) and converts sebocytes toward keratinocyte differentiation, which results in chloracne formation. AHR activation potently upregulates melanogenesis in melanocytes by upregulating the expression of melanogenic enzymes, which results in hyperpigmentation. Because AHR-mediated oxidative stress contributes to these hazardous effects, antioxidative agents may be potentially therapeutic for chloracne and hyperpigmentation.
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http://dx.doi.org/10.3390/ijerph16234864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926551PMC
December 2019

A case of overlapping adult-onset linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic involvement.

Neuropathology 2020 Feb 27;40(1):109-115. Epub 2019 Nov 27.

Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.

Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations.
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http://dx.doi.org/10.1111/neup.12614DOI Listing
February 2020

The CCL20 and CCR6 axis in psoriasis.

Scand J Immunol 2020 Mar 24;91(3):e12846. Epub 2019 Nov 24.

Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.

Psoriasis is a TNF-α/IL-23/IL-17A-mediated inflammatory skin disease that causes a significant socioeconomic burden in afflicted patients. IL-17A-producing immune cells, including Th17 cells, are crucial effector cells in the development of psoriasis. IL-17A stimulates epidermal keratinocytes to produce CCL20, which eventually recruits CCR6 + Th17 cells into the lesional skin. Thus, the CCL20/CCR6 axis works as a driving force that prepares an IL-17A-rich cutaneous milieu. In this review, we summarize the current research topics on the CCL20/CCR6 axis and the therapeutic intervention of this axis for psoriasis.
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http://dx.doi.org/10.1111/sji.12846DOI Listing
March 2020

Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis.

Int J Mol Sci 2019 Oct 31;20(21). Epub 2019 Oct 31.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan.

The aryl hydrocarbon receptor (AHR)/AHR-nuclear translocator (ARNT) system is a sensitive sensor for small molecular, xenobiotic chemicals of exogenous and endogenous origin, including dioxins, phytochemicals, microbial bioproducts, and tryptophan photoproducts. AHR/ARNT are abundantly expressed in the skin. Once activated, the AHR/ARNT axis strengthens skin barrier functions and accelerates epidermal terminal differentiation by upregulating filaggrin expression. In addition, AHR activation induces oxidative stress. However, some AHR ligands simultaneously activate the nuclear factor-erythroid 2-related factor-2 (NRF2) transcription factor, which is a master switch of antioxidative enzymes that neutralizes oxidative stress. The immunoregulatory system governing T-helper 17/22 (Th17/22) and T regulatory cells (Treg) is also regulated by the AHR system. Notably, AHR agonists, such as tapinarof, are currently used as therapeutic agents in psoriasis and atopic dermatitis. In this review, we summarize recent topics on AHR related to atopic dermatitis and psoriasis.
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http://dx.doi.org/10.3390/ijms20215424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862295PMC
October 2019

A Case of Atrophic Dermatofibroma Overexpressing Matrix Metalloproteinase-1.

Case Rep Dermatol 2019 Sep-Dec;11(3):264-267. Epub 2019 Oct 1.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

This case report describes the importance of considering this tumor as one of the differential diagnoses when we encounter a flat and/or atrophic and depressible lesion in the upper portion of the trunk.
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http://dx.doi.org/10.1159/000503136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792423PMC
October 2019

Antioxidants cinnamaldehyde and Galactomyces fermentation filtrate downregulate senescence marker CDKN2A/p16INK4A via NRF2 activation in keratinocytes.

J Dermatol Sci 2019 10 10;96(1):53-56. Epub 2019 Sep 10.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan; Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka, 812-8582, Japan; Division of Skin Surface Sensing, Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jdermsci.2019.09.002DOI Listing
October 2019

The IL-13-OVOL1-FLG axis in atopic dermatitis.

Immunology 2019 12 1;158(4):281-286. Epub 2019 Oct 1.

Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.

Despite sharing interleukin-4 receptor α (IL-4Rα) in their signaling cascades, IL-4 and IL-13 have different functions in atopic inflammation. IL-13 preferentially participates in the peripheral tissues because tissue-resident group 2 innate lymphoid cells produce IL-13 but not IL-4. In contrast, lymph node T follicular helper cells express IL-4 but not IL-13 to regulate B-cell immunity. The dominant microenvironment of IL-13 is evident in the lesional skin of atopic dermatitis (AD). The IL-13-rich local milieu causes barrier dysfunction by down-regulating the OVOL1-filaggrin (FLG) axis and up-regulating the periostin-IL-24 axis. Genome-wide association studies also point to the crucial involvement of the IL-13, OVOL1 and FLG genes in the pathogenesis of AD. Biologics targeting IL-13, such as the anti-IL-4Rα antibody dupilumab and the anti-IL-13 antibody tralokinumab, successfully improve AD lesions and further highlight the importance of IL-13 in the pathogenesis of AD.
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http://dx.doi.org/10.1111/imm.13120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856930PMC
December 2019

IL-4 Augments IL-31/IL-31 Receptor Alpha Interaction Leading to Enhanced Ccl 17 and Ccl 22 Production in Dendritic Cells: Implications for Atopic Dermatitis.

Int J Mol Sci 2019 Aug 20;20(16). Epub 2019 Aug 20.

Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka 812-8582, Japan.

Severe pruritus is a characteristic feature of atopic dermatitis (AD) and is closely related to its activity. Recent studies have shown that IL-31 is a key determinant of pruritus in AD. Anti-IL-31 receptor alpha (IL-31RA) antibody treatment has also been reported to improve pruritus clinically, subsequently contributing to the attenuation of AD disease activity. Therefore, IL-31 has been thought to be an important cytokine for regulating pruritus and AD disease activity; however, how IL-31 is involved in the immune response in AD has remained largely unknown. Epidermal Langerhans cells (LCs) and dermal dendritic cells (DCs) derived from bone marrow cells have been reported to play a critical role in AD pathogenesis. LCs and DCs produce Ccl 17 and Ccl 22, which chemoattract Th2 cells, leading to AD development. Therefore, we aimed to clarify how IL-31/IL-31RA interaction affects Ccl 17 and Ccl 22 production. To test this, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-4, an important cytokine in AD development. We found that IL-31RA expression was upregulated by IL-4 stimulation in a dose-dependent manner in BMDCs. Furthermore, IL-31 upregulates Ccl 17 and Ccl 22 production in the presence of IL-4, whereas IL-31 stimulation alone did not produce Ccl 17 and Ccl 22. These findings suggest that IL-4 mediates IL-31RA expression and IL-31/IL-31RA interaction augments Ccl 17 and Ccl 22 production in BMDCs, which promotes Th2-deviated immune response in AD. Since we previously reported that soybean tar Glyteer, an aryl hydrocarbon receptor (AHR) ligand, impairs IL-4/Stat 6 signaling in BMDCs, we examined whether Glyteer affects IL-31RA expression induced by IL-4 stimulation. Glyteer inhibited upregulation of IL-31RA expression induced by IL-4 stimulation in a dose-dependent manner. Glyteer also inhibited Ccl 17 and Ccl 22 production induced by IL-4 and IL-31 stimulation. Taken together, these findings suggest that Glyteer treatment may improve AD disease activity by impairing IL-31/IL-31RA interaction in DCs.
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http://dx.doi.org/10.3390/ijms20164053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719908PMC
August 2019

Potential role of PM in melanogenesis.

Environ Int 2019 11 6;132:105063. Epub 2019 Aug 6.

Department of Dermatology, Graduate School of Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Fukuoka 812-8582, Japan; Division of Skin Surface Sensing, Department of Dermatology, Graduate School of Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address:

Ambient particulate matter 2.5 (PM) is one of the main components of air pollutants, which can absorb many polycyclic aromatic hydrocarbons and metals. The effect of PM on human skin and its biological significance in skin homeostasis remain incompletely understood. Previous studies demonstrated that PM can activate aryl hydrocarbon receptor (AhR), generate reactive oxygen species, and induce skin inflammation. These processes may be involved in melanocyte homeostasis and melanogenesis. We hypothesize that AhR signaling may be responsible for PM-related hyperpigmentation.
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http://dx.doi.org/10.1016/j.envint.2019.105063DOI Listing
November 2019
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