Publications by authors named "Atsuko Funakoshi"

9 Publications

  • Page 1 of 1

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

Secukinumab promotes engagement of cholecystokinin and its receptor in epidermal keratinocytes of psoriasis patients.

J Dermatol 2020 Dec 13;47(12):1454-1456. Epub 2020 Aug 13.

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

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http://dx.doi.org/10.1111/1346-8138.15552DOI Listing
December 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

Cholecystokinin Downregulates Psoriatic Inflammation by Its Possible Self-Regulatory Effect on Epidermal Keratinocytes.

J Immunol 2019 05 22;202(9):2609-2615. Epub 2019 Mar 22.

Department of Dermatology, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

Cholecystokinin (CCK) is a peptide hormone that functions in digestive organs and the CNS. We previously showed that CCK downregulates peripheral pruritus by suppressing degranulation of mast cells. In this study, we demonstrated that CCK octapeptide (CCK8) was constitutively expressed in the epidermis of normal skin, whereas its expression was lost in acanthotic lesions of psoriasis. In contrast, CCKA receptor (CCKAR), a high-affinity receptor for CCK, was constitutively expressed in the epidermis of psoriatic skin lesions. Expression of CCK was also reduced in skin lesions of an imiquimod (IMQ)-induced psoriatic mouse model. Notably, the expression level of CCK inversely correlated with the severity of epidermal inflammation, raising the possibility that CCK from epidermal keratinocytes suppresses the psoriatic inflammation. To verify this hypothesis, we investigated the effects of sulfated CCK octapeptide (CCK8S) on the development of IMQ-induced psoriatic inflammation. i.p. injection of CCK8S suppressed the IMQ-induced psoriatic inflammation accompanied by reduced mRNA expression of IL-17, IL-22, and IL-6 but not of IL-23. The suppressive effect of CCK8S was completely restored by administration of CCKAR antagonist. In vitro studies showed that exogenous CCK8S suppressed IL-6 production in CCKAR-expressing cultured human keratinocytes, and blocking the endogenous CCK signaling with CCKAR antagonist markedly enhanced IL-6 production. When keratinocytes were stimulated with IL-17, the expression of endogenous CCK was significantly decreased. These findings suggest that CCK physiologically functions as a negative regulator of keratinocyte-based inflammation in an autocrine or paracrine manner, although decreased CCK may pathologically contribute to continuous and aggravated skin lesions such as psoriasis.
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http://dx.doi.org/10.4049/jimmunol.1801426DOI Listing
May 2019

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

Topical application of a vitamin D3 analogue and corticosteroid to psoriasis plaques decreases skin infiltration of TH17 cells and their ex vivo expansion.

J Allergy Clin Immunol 2016 08 11;138(2):517-528.e5. Epub 2016 May 11.

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

Background: Topical combination of a vitamin D3 analogue and corticosteroid is widely used for the treatment of psoriasis, a TH17-mediated disorder, but the underlying mechanism remains unclear.

Objective: We investigated the effect of this topical applicant, focusing on skin-infiltrating TH17 cells.

Methods: In 10 patients with plaque psoriasis, calcipotriol (Cal), betamethasone dipropionate (Bet), or the calcipotriol and betamethasone dipropionate 2-compound formulation (CB) was applied to 3 different psoriatic plaques with similar severity once a day for 14 days. One nonapplied lesion was used as a control. Four-millimeter biopsy specimens were taken from each site, cut into 2 pieces, and subjected to histologic examination and ex vivo expansion of skin-infiltrating T cells with anti-CD3/CD28 antibodies and IL-2.

Results: Clinical, histologic, and IL-17A(+) cell-infiltrate improvement was found in the following order: CB > Cal > Bet > control or CB > Bet > Cal > control. Numbers of ex vivo expanded T cells were decreased by topical application of Bet and CB, and CB exhibited the most suppressive result. Numbers and frequencies of TH17 cells were significantly reduced by CB and Cal, suggesting that Cal has a capacity to preferentially suppress TH17 cells. When the stocked T cells from control samples were stimulated with anti-CD3 antibodies in the presence of Bet, Cal, or both, Cal downmodulated IL-17 and IFN-γ production and tended to upregulate IL-4 and IL-6 without apoptosis, but Bet inhibited production of these cytokines with apoptosis.

Conclusion: These findings suggest that Cal and Bet have different effects on T cells to normalize psoriatic changes, with decreased TH17 cell expansion in the skin lesions.
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http://dx.doi.org/10.1016/j.jaci.2016.03.048DOI Listing
August 2016

Exacerbation of alopecia areata during pegylated interferon alpha-2b and ribavirin therapy, possibly due to the collapse of hair follicle immune privilege.

Eur J Dermatol 2014 Sep-Oct;24(5):631-3

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

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http://dx.doi.org/10.1684/ejd.2014.2421DOI Listing
August 2015

Birth, life, and death of the MAGE3 hypothesis of alopecia areata pathobiology.

J Dermatol Sci 2013 Dec 8;72(3):327-30. Epub 2013 Aug 8.

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

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http://dx.doi.org/10.1016/j.jdermsci.2013.07.014DOI Listing
December 2013

CXCL10 produced from hair follicles induces Th1 and Tc1 cell infiltration in the acute phase of alopecia areata followed by sustained Tc1 accumulation in the chronic phase.

J Dermatol Sci 2013 Feb 26;69(2):140-7. Epub 2012 Dec 26.

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

Background: Alopecia areata (AA) is an organ-specific and cell-mediated autoimmune disease. T lymphocytes densely surround lesional hair bulbs, which is histologically referred to as "swarm of bees". However, pathomechanisms of "swarm of bees" are still uncertain.

Objective: We investigated the pathological mechanisms of "swarm of bees", focusing on T-cell chemotaxis so that inhibition of chemotaxis may be strong candidate of novel treatments for AA.

Methods: We investigate the expression of chemokine receptors on T cells obtained from peripheral blood mononuclear cells (PBMCs) and skin infiltrating cells in AA patients. In addition, real-time chemotaxis assay was also demonstrated.

Results: In PBMCs, the frequency of CXCR3+CD4+ T cells (Th1) was significantly higher in acute-phase AA than in chronic-phase AA or healthy control, while CXCR3+CD8+ T cells (Tc1) were significantly increased in chronic-phase AA. In the skin lesions of acute-phase AA, CXCR3+CD4+ and CXCR3+CD8+ T cells infiltrated in the juxta-follicular area. In chronic-phase AA, CXCR3+CD8+ T cells dominated the infiltrate around hair bulbs, possibly contributing to the prolonged state of hair loss. Lymphocytes obtained from a lesional skin of acute-phase AA contained CXCR3+CD4+ and CXCR3+CD8+ T cells at higher percentages than those of PBMCs, suggesting preferential emigration from the blood. Immunohistochemical and real-time RT-PCR studies demonstrated that hair follicles of acute-phase AA expressed a high level of Th1-associated chemokine CXCL10. By chemotaxis assay, freshly isolated PBMCs from acute-phase AA patients had a strong velocity of chemotaxis toward CXCL10 with increased expression of F-actin.

Conclusions: These results suggest that the increased production of CXCL10 from hair follicles induces preferential infiltrates of highly chemoattracted Th1 and Tc1 cells in the acute phase of AA, and Tc1 infiltration remains prolonged in the chronic phase.
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http://dx.doi.org/10.1016/j.jdermsci.2012.12.003DOI Listing
February 2013
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