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Atsushi Otsuka, Saeko Nakajima,
Masato Kubo,
Gyohei Egawa,
Tetsuya Honda,
Akihiko Kitoh,
Takashi Nomura,
Sho Hanakawa,
Catharina Sagita Moniaga,
Bongju Kim,
Satoshi Matsuoka,
Takeshi Watanabe,
Yoshiki Miyachi,
Kenji Kabashima
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ABSTRACT: The relative contributions of basophils and dendritic cells in Th2 skewing to foreign antigen exposure remain unclear. Here we report the ability of basophils to induce Th2 polarization upon epicutaneous sensitization with different antigens using basophil conditionally depleted Bas TRECK transgenic mice. Basophils are responsible for Th2 skewing to haptens and peptide antigens, but not protein antigens in vivo. Consistent with this, basophils cannot take up or process ovalbumin protein in significant quantities, but present ovalbumin peptide to T cells for Th2 differentiation via major histocompatibility complex class II. Intriguingly, basophils promote Th2 skewing upon ovalbumin protein exposure in the presence of dendritic cells. Taken together, our results suggest that basophils alone are able to induce Th2 skewing with haptens and peptide antigens but require dendritic cells for the induction of Th2 for protein antigens upon epicutaneous immunization.
Nature Communications 04/2013; 4:1738. · 7.40 Impact Factor
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Tomoko Mori,
Kenji Kabashima,
Shoko Fukamachi,
Etsushi Kuroda,
Jun-Ichi Sakabe,
Miwa Kobayashi, Saeko Nakajima,
Kazuhisa Nakano,
Yoshiya Tanaka,
Sho Matsushita,
Motonobu Nakamura,
Yoshiki Tokura
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ABSTRACT: 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.
Journal of dermatological science 04/2013; · 3.71 Impact Factor
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ABSTRACT: Epidermal barrier abnormality due to filaggrin deficiency is an important predisposing factor in the development of atopic dermatitis (AD). In addition, the expression of thymic stromal lymphopoietin (TSLP) in keratinocytes (KCs), induced by barrier disruption, can promote type 2 helper T-cell polarization. Protease activity, including protease-activated receptor-2 (PAR-2), is also known to be involved in epidermal barrier function in AD. However, to our knowledge, the relationship between protease activity and filaggrin deficiency from the perspective of AD has not been elucidated. Flaky tail (Flg(ft)) mice, known to have a mutation in the filaggrin gene, were used to assess the role of protease in KCs in the steady state and the mite-induced AD-like skin inflammation model. In the steady state, the expression and activity levels of endogenous proteases, kallikreins 5, 7, and 14, in the skin and TSLP were higher in Flg(ft) than in control mice. In addition, activation of PAR-2 by its agonist induced the production of TSLP in KCs of Flg(ft) mice, which was abrogated by a newly developed PAR-2 antagonist. Application of the PAR-2 antagonist improved symptoms and basophil accumulation in Flg(ft) mice treated with mite extracts. These results suggest that possibly through the PAR-2 activation in KCs, filaggrin deficiency induces TSLP production and basophil accumulation, which play important roles in the establishment of AD.
American Journal Of Pathology 01/2013; · 4.89 Impact Factor
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Saeko Nakajima,
Botond Z Igyártó,
Tetsuya Honda,
Gyohei Egawa,
Atsushi Otsuka,
Mariko Hara-Chikuma,
Norihiko Watanabe,
Steven F Ziegler,
Michio Tomura,
Kayo Inaba,
Yoshiki Miyachi,
Daniel H Kaplan,
Kenji Kabashima
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ABSTRACT: The clarification of cutaneous dendritic cell subset and the role of thymic stromal lymphopoietin (TSLP) signaling in epicutaneous sensitization with protein antigens, as in the development of atopic dermatitis, is a crucial issue.
Because TSLP is highly expressed in the vicinity of Langerhans cells (LCs), we sought to clarify our hypothesis that LCs play an essential role in epicutaneous sensitization with protein antigens through TSLP signaling.
By using Langerin-diphtheria toxin receptor knock-in mice and human Langerin-diphtheria toxin A transgenic mice, we prepared mice deficient in LCs. We also prepared mice deficient in TSLP receptors in LCs by using TSLP receptor-deficient mice with bone marrow chimeric technique. We applied these mice to an ovalbumin (OVA)-induced epicutaneous sensitization model.
Upon the epicutaneous application of OVA, conditional LC depletion attenuated the development of clinical manifestations as well as serum OVA-specific IgE increase, OVA-specific T-cell proliferation, and IL-4 mRNA expression in the draining lymph nodes. Consistently, even in the steady state, permanent LC depletion resulted in decreased serum IgE levels, suggesting that LCs mediate the T(H)2 local environment. In addition, mice deficient in TSLP receptors on LCs abrogated the induction of OVA-specific IgE levels upon epicutaneous OVA sensitization.
LCs initiate epicutaneous sensitization with protein antigens and induce T(H)2-type immune responses via TSLP signaling.
The Journal of allergy and clinical immunology 02/2012; 129(4):1048-55.e6. · 9.17 Impact Factor
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Saeko Nakajima,
Hideaki Watanabe,
Mikiko Tohyama,
Kazunari Sugita,
Masafumi Iijima,
Koji Hashimoto,
Yoshiki Tokura,
Youichi Nishimura,
Hiromi Doi,
Miki Tanioka,
Yoshiki Miyachi,
Kenji Kabashima
Archives of dermatology 09/2011; 147(9):1110-2. · 4.76 Impact Factor
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Atsushi Otsuka,
Masato Kubo,
Tetsuya Honda,
Gyohei Egawa, Saeko Nakajima,
Hideaki Tanizaki,
Bongju Kim,
Satoshi Matsuoka,
Takeshi Watanabe,
Susumu Nakae,
Yoshiki Miyachi,
Kenji Kabashima
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ABSTRACT: The role of mast cells (MCs) in contact hypersensitivity (CHS) remains controversial. This is due in part to the use of the MC-deficient Kit (W/Wv) mouse model, since Kit (W/Wv) mice congenitally lack other types of cells as a result of a point mutation in c-kit. A recent study indicated that the intronic enhancer (IE) for Il4 gene transcription is essential for MCs but not in other cell types. The aim of this study is to re-evaluate the roles of MCs in CHS using mice in which MCs can be conditionally and specifically depleted. Transgenic Mas-TRECK mice in which MCs are depleted conditionally were newly generated using cell-type specific gene regulation by IE. Using this mouse, CHS and FITC-induced cutaneous DC migration were analyzed. Chemotaxis assay and cytoplasmic Ca²⁺ imaging were performed by co-culture of bone marrow-derived MCs (BMMCs) and bone marrow-derived dendritic cells (BMDCs). In Mas-TRECK mice, CHS was attenuated when MCs were depleted during the sensitization phase. In addition, both maturation and migration of skin DCs were abrogated by MC depletion. Consistently, BMMCs enhanced maturation and chemotaxis of BMDC in ICAM-1 and TNF-α dependent manners Furthermore, stimulated BMDCs increased intracellular Ca²⁺ of MC upon direct interaction and up-regulated membrane-bound TNF-α on BMMCs. These results suggest that MCs enhance DC functions by interacting with DCs in the skin to establish the sensitization phase of CHS.
PLoS ONE 01/2011; 6(9):e25538. · 4.09 Impact Factor
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Hideaki Tanizaki,
Gyohei Egawa,
Kayo Inaba,
Tetsuya Honda, Saeko Nakajima,
Catharina Sagita Moniaga,
Atsushi Otsuka,
Toshimasa Ishizaki,
Michio Tomura,
Takeshi Watanabe,
Yoshiki Miyachi,
Shuh Narumiya,
Takaharu Okada,
Kenji Kabashima
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ABSTRACT: Dendritic cells (DCs) are essential for the initiation of acquired immune responses through antigen acquisition, migration, maturation, and T-cell stimulation. One of the critical mechanisms in this response is the process actin nucleation and polymerization, which is mediated by several groups of proteins, including mammalian Diaphanous-related formins (mDia). However, the role of mDia in DCs remains unknown. Herein, we examined the role of mDia1 (one of the isoforms of mDia) in DCs. Although the proliferation and maturation of bone marrow-derived DCs were comparable between control C57BL/6 and mDia1-deficient (mDia1(-/-)) mice, adhesion and spreading to cellular matrix were impaired in mDia1(-/-) bone marrow-derived DCs. In addition, fluorescein isothiocyanate-induced cutaneous DC migration to draining lymph nodes in vivo and invasive migration and directional migration to CCL21 in vitro were suppressed in mDia1(-/-) DCs. Moreover, sustained T-cell interaction and T-cell stimulation in lymph nodes were impaired by mDia1 deficiency. Consistent with this, the DC-dependent delayed hypersensitivity response was attenuated by mDia1-deficient DCs. These results suggest that actin polymerization, which is mediated by mDia1, is essential for several aspects of DC-initiated acquired immune responses.
Blood 09/2010; 116(26):5875-84. · 9.90 Impact Factor
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The Journal of allergy and clinical immunology 08/2010; 126(2):408-10. · 9.17 Impact Factor
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Archives of dermatology 06/2010; 146(6):686-7. · 4.76 Impact Factor
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Saeko Nakajima,
Tetsuya Honda,
Daiji Sakata,
Gyohei Egawa,
Hideaki Tanizaki,
Atsushi Otsuka,
Catharina Sagita Moniaga,
Takeshi Watanabe,
Yoshiki Miyachi,
Shuh Narumiya,
Kenji Kabashima
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ABSTRACT: PGI(2), which exerts its actions via its specific Gs-coupled I prostanoid receptor (IP), is known to be present in the lymph nodes, but its roles in acquired cutaneous immune responses remain unclear. To investigate the role of PGI(2)-IP signaling in cutaneous immune responses, we applied IP-deficient (Ptgir(-/-)) mice to contact hypersensitivity as a model of acquired immune response and found that Ptgir(-/-) mice exhibited a significantly decreased contact hypersensitivity response. Lymph node cells from sensitized Ptgir(-/-) mice exhibited decreased IFN-gamma production and a smaller T-bet(+) subset compared with control mice. PGI synthase and IP expression were detected in dendritic cells and T cells, respectively, by quantitative real-time PCR analysis, suggesting that PGI(2) produced by dendritic cells acts on IP in T cells. In fact, in vitro Th1 differentiation was enhanced by an IP agonist, and this enhancement was nullified by protein kinase A inhibitor. These results suggest that PGI(2)-IP signaling promotes Th1 differentiation through a cAMP-protein kinase A pathway and thereby initiates acquired cutaneous immune responses.
The Journal of Immunology 05/2010; 184(10):5595-603. · 5.79 Impact Factor
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The Journal of allergy and clinical immunology 03/2010; 125(5):1154-1156.e2. · 9.17 Impact Factor
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Catharina Sagita Moniaga,
Gyohei Egawa,
Hiroshi Kawasaki,
Mariko Hara-Chikuma,
Tetsuya Honda,
Hideaki Tanizaki, Saeko Nakajima,
Atsushi Otsuka,
Hiroyuki Matsuoka,
Akiharu Kubo,
Jun-ichi Sakabe,
Yoshiki Tokura,
Yoshiki Miyachi,
Masayuki Amagai,
Kenji Kabashima
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[hide abstract]
ABSTRACT: The barrier abnormality, a loss-of-function mutation in the gene encoding filaggrin (FLG), which is linked to the incidence of atopic dermatitis (AD), is a recently discovered but important factor in the pathogenesis of AD. Flaky tail (Flg(ft)) mice, essentially deficient in filaggrin, have been used to investigate the role of filaggrin on AD. However, the relevancy of Flg(ft) mice to human AD needs to be determined further. In this study, we observed the clinical manifestations of Flg(ft) mice in the steady state and their cutaneous immune responses against external stimuli, favoring human AD. Under specific pathogen-free conditions, the majority of Flg(ft) mice developed clinical and histological eczematous skin lesions similar to human AD with outside-to-inside skin barrier dysfunction evaluated by newly devised methods. In addition, cutaneous hapten-induced contact hypersensitivity as a model of acquired immune response and a mite extract-induced dermatitis model physiologically relevant to a human AD were enhanced in Flg(ft) mice. These results suggest that the Flg(ft) mouse genotype has potential as an animal model of AD corresponding with filaggrin mutation in human AD.
American Journal Of Pathology 03/2010; 176(5):2385-93. · 4.89 Impact Factor
