難治性かゆみにおける脊髄グリア細胞の役割の解明と新規治療法の開発

2015 Fiscal Year Annual Research Report

• Project/Area Number: 25460727
• Research Institution: Juntendo University
• Principal Investigator: 高森 建二 順天堂大学, 医学部, 教授 (40053144)
• Co-Investigator(Kenkyū-buntansha): 冨永 光俊 順天堂大学, 医学(系)研究科(研究院), 准教授 (50468592) ; 加茂 敦子 順天堂大学, 医学(系)研究科(研究院), 助教 (50614088)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 難治性かゆみ / 脊髄後角 / ミクログリア / アトピー性皮膚炎 / ミノサイクリン

Outline of Annual Research Achievements

本年度は、ミクログリア活性化阻害剤であるminocyclineの髄腔内投与及び経口投与による止痒及び皮膚炎改善効果について検討した。アトピー性皮膚炎(AD)未発症NC/Ngaマウスと比較して、ダニ虫体成分(Dfb)含有軟膏の反復塗布によって誘発したAD様症状を呈するNC/Ngaマウス(Dfb-NC/Nga)の脊髄後角においてIba1陽性ミクログリア数が増加することが免疫組織学的解析により明らかとなった。
Dfb-NC/Ngaマウスの髄腔内にminocyclineを5 μg/5 μL及び50 μg/5 μLで週3回、2週間投与すると、コントロール群（溶媒投与群）と比較して、minocycline投与群において、投与量依存的に有意な掻破行動の抑制と皮膚炎の改善を示した。50 μg/5 μL minocyclineの髄腔内投与群では、脊髄後角において増加していたIba1陽性ミクログリア数が減少することが明らかとなった。さらに、minocyclineの経口投与は投与量依存的にかゆみ行動の抑制とIba1陽性ミクログリア数の減少傾向を示した。このように、脊髄、特に脊髄後角のミクログリアは少なくともADにおける難治性かゆみの発症に関与すること、脊髄内ミクログリアがADにおける難治性かゆみの治療標的のひとつに成り得ることが示唆された。

Research Products

• [Journal Article] Intrathecal minocycline suppresses itch-related behavior and improves dermatitis in atopic dermatitis model mouse. (2016)
  • Author(s): Torigoe K, Tominaga M, Ko KC, Takahashi N, Matsuda H, Hayashi R, Ogawa H, Takamori K.
  • Journal Title: J Invest Dermatol Volume: 136 Pages: 879～881
  • DOI: 10.1016/j.jid.2015.12.037.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Neurotropin suppresses itch-related behavior in NC/Nga mice with atopic dermatitis-like symptoms. (2016)
  • Author(s): Kamo A, Tominaga M, Matsuda H, Kina K, Kamata Y, Umehara Y, Ogawa H, Takamori K.
  • Journal Title: J Dermatol Sci Volume: 81 Pages: 212～215
  • DOI: 10.1016/j.jdermsci.2015.11.014.
  • Peer Reviewed
• [Journal Article] Possible anti-pruritic mechanisms of cyclosporine A in atopic dermatitis. (2016)
  • Author(s): Ko KC, Tominaga M, Kamata Y, Umehara Y, Matsuda H, Takahashi N, Kina K, Ogawa M, Ogawa H, Takamori K.
  • Journal Title: Acta Derm Venereol Volume: 未定 Pages: 未定
  • DOI: 10.2340/00015555-2318.
  • Peer Reviewed / Open Access
• [Journal Article] Definition of Sensitive Skin: an Expert Position Paper from the Special Interest Group on Sensitive Skin of the International Forum for the Study of Itch. (2016)
  • Author(s): Misery L, Stander S, Szepietowski JC, Reich A, Wallengren J, Evers AW, Takamori K, Brenaut E, Gall-Ianotto CL, Fluhr J, Berardesca E, Weisshaar E.
  • Journal Title: Acta Derm Venereol Volume: 未定 Pages: 未定
  • DOI: 10.2340/00015555-2397.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Skin pH is the master switch of kallikrein 5-mediated skin barrier destruction in a murine atopic dermatitis model. (2016)
  • Author(s): Jang H, Matsuda A, Jung K, Karasawa K, Matsuda K, Oida K, Ishizaka S, Ahn G, Amagai Y, Moon C, Kim SH, Arkwright PD, Takamori K, Matsuda H, Tanaka A.
  • Journal Title: J Invest Dermatol Volume: 136 Pages: 127～135
  • DOI: 10.1038/JID.2015.363.
  • Peer Reviewed
• [Journal Article] Tumour-promoting activity of polycyclic aromatic hydrocarbons and their oxygenated or nitrated derivatives. (2016)
  • Author(s): Misaki K, Takamura-Enya T, Ogawa H, Takamori K, Yanagida M.
  • Journal Title: Mutagenesis Volume: 31 Pages: 205～213
  • DOI: 10.1093/mutage/gev076.
  • Peer Reviewed
• [Journal Article] TEX101, a glycoprotein essential for sperm fertility, is required for stable expression of Ly6k on testicular germ cells. (2016)
  • Author(s): Endo S, Yoshitake H, Tsukamoto H, Matsuura H, Kato K, Sakuraba M, Takamori K, Fujiwara H, Takeda S, Araki Y.
  • Journal Title: Sci Rep Volume: 23 Pages: 23616
  • DOI: 10.1038/srep23616.
  • Peer Reviewed / Open Access
• [Journal Article] ANNALS EXPRESS: Simple quantitation for potential serum disease biomarker peptides, primarily identified by a peptidomics approach in the serum with hypertensive disorders of pregnancy. (2016)
  • Author(s): Hamamura K, Nonaka D, Ishikawa H, Banzai M, Yanagida M, Nojima M, Yoshida K, Lee LJ, Tanaka K, Takamori K, Takeda S, Araki Y.
  • Journal Title: Ann Clin Biochem Volume: 53 Pages: 85～96
  • DOI: 10.1177/0004563215583697.
  • Peer Reviewed
• [Journal Article] Inhibition of each module of connective tissue growth factor as a potential therapeutic target for rheumatoid arthritis. (2016)
  • Author(s): Miyashita T, Morimoto S, Fujishiro M, Hayakawa K, Suzuki S, Ikeda K, Miyazawa K, Morioka M, Takamori K, Ogawa H, Sekigawa I, Takasaki Y.
  • Journal Title: Autoimmunity Volume: 49 Pages: 109～114
  • DOI: 10.3109/08916934.2015.1113405.
  • Peer Reviewed
• [Journal Article] Cathelicidin LL-37 induces semaphorin 3A production in human epidermal keratinocytes: implications for possible application to pruritus. (2015)
  • Author(s): Umehara Y, Kamata Y, Tominaga M, Niyonsaba F, Ogawa H, Takamori K.
  • Journal Title: J Invest Dermatol Volume: 135 Pages: 2887～2890
  • DOI: 10.1038/jid.2015.243.
  • Peer Reviewed
• [Journal Article] Retinoid-related orphan receptor alpha is involved in semaphorin 3A expression in normal human epidermal keratinocytes. (2015)
  • Author(s): Kamata Y, Tominaga M, Umehara Y, Negi O, Ogawa H, Takamori K.
  • Journal Title: J Dermatol Sci Volume: 79 Pages: 84～86
  • DOI: 10.1016/j.jdermsci.2015.03.015.
  • Peer Reviewed
• [Journal Article] Topical application of Tenshino-softgelTM reduces epidermal nerve fiber density in a chronic dry skin model mouse. (2015)
  • Author(s): Noguchi A, Tominaga M, Ko KC, Matsuda H, Suga Y, Ogawa H, Takamori K.
  • Journal Title: Journal of Cosmetics, Dermatological Sciences and Applications Volume: 5 Pages: 254～261
  • DOI: 10.4236/jcdsa.2015.54031
  • Peer Reviewed / Open Access
• [Journal Article] Tinea Faciei Caused by Trichophyton mentagrophytes (Molecular Type Arthroderma benhamiae) Mimics Impetigo : A Case Report and Literature Review of Cases in Japan. (2015)
  • Author(s): Kimura U, Yokoyama K, Hiruma M, Kano R, Takamori K, Suga Y.
  • Journal Title: Med Mycol J Volume: 56 Pages: 1～5
  • DOI: 10.3314/mmj.56.E1.
  • Peer Reviewed
• [Journal Article] Chemical characterization of N-linked oligosaccharide as the antigen epitope recognized by an anti-sperm auto-monoclonal antibody, Ts4. (2015)
  • Author(s): Yoshitake H, Hashii N, Kawasaki N, Endo S, Takamori K, Hasegawa A, Fujiwara H, Araki Y.
  • Journal Title: PLoS One Volume: 10 Pages: e0133784
  • DOI: 10.1371/journal.pone.0133784.
  • Peer Reviewed / Open Access
• [Journal Article] Properties and functions of lactosylceramide from mouse neutrophils. (2015)
  • Author(s): Iwabuchi K, Masuda H, Kaga N, Nakayama H, Matsumoto R, Iwahara C, Yoshizaki F, Tamaki Y, Kobayashi T, Hayakawa T, Ishii K, Yanagida M, Ogawa H, Takamori K.
  • Journal Title: Glycobiology Volume: 25 Pages: 655～668
  • DOI: 10.1093/glycob/cwv008.
  • Peer Reviewed
• [Presentation] Itching in atopic dermatitis: what’s new. (2016)
  • Author(s): Takamori K.
  • Organizer: American Academy of Dermatology (AAD) 47th Annual Meeting
  • Place of Presentation: Washington Convention Center (Washington D.C.)
  • Year and Date: 2016-03-04 – 2016-03-08
  • Int'l Joint Research / Invited
• [Presentation] Electrophysiological characterization of BNP- and GRP-responsive dorsal horn neurons in spinal itch transmission. (2015)
  • Author(s): Tominaga M, Kusube F, Kawasaki H, Yamakura F, Naito H, Ogawa H, Tomooka Y, Takamori K
  • Organizer: 第40回日本研究皮膚科学会
  • Place of Presentation: 岡山コンベンションセンター（岡山）
  • Year and Date: 2015-12-11 – 2015-12-13
• [Presentation] Inhibitory factors in semaphorin 3A expression of human epidermal keratinocytes. (2015)
  • Author(s): Kamata Y, Umehara Y, Tominaga M, Negi O, Ogawa H, Takamori K.
  • Organizer: 第40回日本研究皮膚科学会
  • Place of Presentation: 岡山コンベンションセンター（岡山）
  • Year and Date: 2015-12-11 – 2015-12-13
• [Presentation] Effects of antimicrobial peptides on expression of axon guidance molecules in normal human epidermal keratinocytes. (2015)
  • Author(s): Umehara Y, Kamata Y, Tominaga M, Niyonsaba F, Ogawa H, Takamori K.
  • Organizer: 第40回日本研究皮膚科学会
  • Place of Presentation: 岡山コンベンションセンター（岡山）
  • Year and Date: 2015-12-11 – 2015-12-13
• [Presentation] Host defense protein S100A7/psoriasin regulates pores in the epidermis: aquaporins and tight junctions. (2015)
  • Author(s): Hattori F, Ikeda S, Okumura K, Tominaga M, Takamori K, Ogawa H, Okamoto K, Niyonsaba F.
  • Organizer: 第40回日本研究皮膚科学会
  • Place of Presentation: 岡山コンベンションセンター（岡山）
  • Year and Date: 2015-12-11 – 2015-12-13
• [Presentation] ヒト表皮角化細胞を用いたセマフォリン3A遺伝子の近位プロモーター領域の解析. (2015)
  • Author(s): 鎌田弥生、冨永光俊、梅原芳恵、高森建二.
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド(神戸)
  • Year and Date: 2015-12-01 – 2015-12-04
• [Presentation] ヒトiPS細胞からのかゆみ末梢神経誘導法の開発. (2015)
  • Author(s): 梅原芳恵、冨永光俊、松田浩則、鎌田弥生、髙森建二.
  • Organizer: 第38回日本分子生物学会年会、第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド(神戸)
  • Year and Date: 2015-12-01 – 2015-12-04
• [Presentation] H1-ヒスタミン受容体拮抗薬による軸索ガイダンス分子の発現調節作用. (2015)
  • Author(s): 鎌田弥生、坂口安澄、梅原芳恵、冨永光俊、小川秀興、高森建二.
  • Organizer: 第45回日本皮膚アレルギー・接触皮膚炎学会総会学術大会
  • Place of Presentation: 島根県民会館(島根)
  • Year and Date: 2015-11-20 – 2015-11-22
• [Presentation] 抗菌ペプチドLL-37は培養正常ヒト表皮角化細胞における神経反発因子semaphorin 3Aの発現を促進する. (2015)
  • Author(s): 梅原芳恵、鎌田弥生、冨永光俊、Francois Niyonsaba、小川秀興、高森建二.
  • Organizer: 第45回日本皮膚アレルギー・接触皮膚炎学会総会学術大会
  • Place of Presentation: 島根県民会館(島根)
  • Year and Date: 2015-11-20 – 2015-11-22
• [Presentation] Intrathecal minocycline attenuates itch in atopic dermatitis mouse model. (2015)
  • Author(s): Torigoe K, Tominaga M, Takamori K.
  • Organizer: 8th World Congress on Itch
  • Place of Presentation: Nara Prefecture New Public Hall (Nara)
  • Year and Date: 2015-09-27 – 2015-09-29
  • Int'l Joint Research
• [Presentation] Correlation of plasma granzyme B levels with pruritus of atopic dermatitis. (2015)
  • Author(s): Kamata Y, Kimura U, Matsuda H, Tengara S, Tominaga M, Ogawa H, Takamori K.
  • Organizer: 8th World Congress on Itch
  • Place of Presentation: Nara Prefecture New Public Hall (Nara)
  • Year and Date: 2015-09-27 – 2015-09-29
  • Int'l Joint Research
• [Presentation] The effects of cathelicidin LL-37 on semaphorin 3A expression in normal human epidermal keratinocytes. (2015)
  • Author(s): Umehara Y, Kamata Y, Tominaga M, Niyonsaba F, Ogawa H, Takamori K.
  • Organizer: 8th World Congress on Itch
  • Place of Presentation: Nara Prefecture New Public Hall (Nara)
  • Year and Date: 2015-09-27 – 2015-09-29
  • Int'l Joint Research
• [Presentation] Pleiotropic action of cyclosporine on pruritus of atopic dermatitis. (2015)
  • Author(s): Tominaga M, Ko KC, Kamata Y, Umehara Y, Matsuda H, Takahashi N, Kina K, Ogawa M, Ogawa H, Takamori K.
  • Organizer: 8th World Congress on Itch
  • Place of Presentation: Nara Prefecture New Public Hall (Nara)
  • Year and Date: 2015-09-27 – 2015-09-29
  • Int'l Joint Research
• [Presentation] 血漿グランザイム濃度とアトピー性皮膚炎の重症度の相関解析. (2015)
  • Author(s): 鎌田弥生、木村有太子、松田浩則、Suhandy Tengara、加茂 敦子、冨永光俊、高森建二.
  • Organizer: 第20回日本病態プロテアーゼ学会
  • Place of Presentation: ANAクラウンプラザホテルグランコート名古屋（名古屋）
  • Year and Date: 2015-08-21 – 2015-08-22
• [Presentation] The antimicrobial peptide cathelicidin LL-37 induces semaphorin 3A production in normal human epidermal keratinocytes. (2015)
  • Author(s): Umehara Y, Kamata Y, Tominaga M, Niyonsaba F, Ogawa H, Takamori K.
  • Organizer: 2015 SOCIETY FOR INVESTIGATIVE DERMATOLOGY (SID) annual meeting
  • Place of Presentation: HILTON Atlanta (Georgia, USA)
  • Year and Date: 2015-05-06 – 2015-05-09
  • Int'l Joint Research
• [Presentation] Effects of H1-antihistamines on expression of axon guidance molecules in normal human epidermal keratinocytes. (2015)
  • Author(s): Kamata Y, Sakaguchi A, Umehara Y, Tominaga M, Ogawa H, Takamori K.
  • Organizer: 2015 SOCIETY FOR INVESTIGATIVE DERMATOLOGY (SID) annual meeting
  • Place of Presentation: HILTON Atlanta (Georgia, USA)
  • Year and Date: 2015-05-06 – 2015-05-09
  • Int'l Joint Research
• [Book] Itch-Management in Clinical Practice (2016)
  • Author(s): Kamata Y, Tominaga M, Takamori K.
  • Total Pages: 未定
  • Publisher: Medical and Scientific Publishers
• [Book] Pruritus Second Edition (2016)
  • Author(s): Tominaga M, Takamori K.
  • Total Pages: 未定
  • Publisher: Springer Science+Business Media
• [Book] 抗ヒスタミン薬．膠原病・リウマチ・アレルギー研修ノート (2016)
  • Author(s): 鎌田弥生、髙森建二.
  • Total Pages: 未定
  • Publisher: 診断と治療社
• [Remarks] 順天堂大学大学院医学研究科環境医学研究所 高森建二研究グループ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/kankyo_igaku/k4_takamori.html