Analysis of the role of S100A8/A9 and its novel receptors in chronic inflammation in atopic dermatitis

• Project/Area Number: 26860899
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Tokyo Medical University
• Principal Investigator: YAMAMOTO Mami 東京医科大学, 医学部, 助教 (60421062)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: アトピー性皮膚炎 / S100A8/A9

Outline of Final Research Achievements

Previously, we reported a positive feedback loop between S100A8/A9 and proinflammatory cytokines mediated by extracellular matrix metalloproteinase inducer (EMMPRIN), an S100A9 receptor. Therefore, we assumed that S100A8/A9 plays an important role in the chronic inflammation that arises from barrier disruption in atopic dermatitis. In this study, we identified neuroplastin-β (NPTNβ) as a novel S100A8 receptor. The S100A8-NPTNβ signal activated keratinocyte proliferation, while the S100A9-EMMPRIN signaling pathway induced skin inflammation. NPTNβ and EMMPRIN formed homodimers and a heterodimer. S100A8 and S100A9 were strongly expressed and co-localized with these receptors in the lesional skin of atopic dermatitis. These results indicate that NPTNβ and EMMPRIN form a functional heterodimeric receptor for S100A8/A9 and play a critical role in atopic dermatitis.

Research Products

• [Journal Article] Identification of an S100A8 receptor neuroplastin-β and its heterodimer formation with EMMPRIN. (2016)
  • Author(s): Sakaguchi M, Yamamoto M, Miyai M, Maeda T, Hiruma J, Murata H, Kinoshita R, Ruma IM, Putranto EW, Inoue Y, Morizane S, Huh NH, Tsuboi R, Hibino T.
  • Journal Title: J Invest Dermatol. Volume: 136 Issue: 11 Pages: 2240-2250
  • DOI: 10.1016/j.jid.2016.06.617
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] アトピー性皮膚炎におけるS100A8/A9と新規レセプターの役割解明 (2015)
  • Author(s): 山本真実
  • Journal Title: アレルギーの臨床 Volume: 35 Pages: 958-961
• [Presentation] 皮膚のバリア機能の研究を通じて感じたこと：臨床医が基礎研究をする意義 (2016)
  • Author(s): 山本真実
  • Organizer: 第178回東京医科大学医学会総会 100周年記念特別シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2016-11-05
  • Invited
• [Presentation] インフラマゾームの構成要素であるNOD2は乾燥状態に反応し、炎症を誘導する (2016)
  • Author(s): 山本真実、宮井雅史、比留間潤一郎、阪口政清、山西治代、坪井良治、日比野利彦
  • Organizer: 第115回日本皮膚科学会総会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-04
• [Presentation] NOD2 inflammasome is associated with inflammatory and immune reactions in atopic dermatitis (2016)
  • Author(s): Yamamoto M, Miyai M, Yamanishi H, Sakaguchi M, Hiruma J, Tsuboi R, Hibino T:
  • Organizer: The 75th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Scottsdale, Arizona
  • Year and Date: 2016-05-14
  • Int'l Joint Research
• [Presentation] NLRC4 inflammasome is involved in the pathophysiology of psoriasis (2016)
  • Author(s): Hiruma J, Miyai M, Yamamoto M, Motoyama A, Sakaguchi M, Yamanishi H, Tsuboi R, Hibino T
  • Organizer: The 75th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Scottsdale, Arizona
  • Year and Date: 2016-05-14
  • Int'l Joint Research
• [Presentation] Mechanism of S100A9 induction in the skin with atopic dermatitis - involvement of NOD2 inflammasome activation - (2015)
  • Author(s): Yamamoto-Tanaka M, Miyai M, Sawane M, Yamanishi H, Sakaguchi M, Tsuboi R, Hibino T
  • Organizer: The 40th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 岡山
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] NOD2 inflammasome is up-regulated in the skin with atopic dermatitis (2015)
  • Author(s): Miyai M, Yamamoto-Tanaka M, Sawane M, Yamanishi H, Sakaguchi M, Tsuboi R, Hibino T
  • Organizer: The 40th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 岡山
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] Analysis of domain structure-function relationship in NOD-like receptor family members (2015)
  • Author(s): Hiruma J, Miyai M, Yamamoto-Tanaka M, Tsuboi R, Hibino T
  • Organizer: The 40th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 岡山
  • Year and Date: 2015-12-11
  • Int'l Joint Research
• [Presentation] 表皮特異的メソトリプシンは角層剥離を制御する - 隠された角層剥離メカニズム- (2015)
  • Author(s): 宮井雅史、山西治代、松元有羽子、田中（山本）真実、坪井良治、日比野利彦
  • Organizer: 第38回日本分子生物学会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] The role of inflammasome in atopic dermatitis (2015)
  • Author(s): Yamamoto-Tanaka M, Sakaguchi M, Miyai M, Hiruma J, Hibino T, Tsuboi R
  • Organizer: 第29回表皮細胞研究会
  • Place of Presentation: 佐賀
  • Year and Date: 2015-11-14
• [Presentation] S100A8/A9 induces skin inflammation and keratinocyte proliferation via neuroplastin-beta/EMMPRIN heterodimer receptor in atopic dermatitis (2015)
  • Author(s): Miyai M, Sakaguchi M, Yamamoto-Tanaka M, Maeda T, Hiruma J, Tsuboi R, Hibino T
  • Organizer: The 45th Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Rotterdam, The Netherlands
  • Year and Date: 2015-09-10
  • Int'l Joint Research
• [Presentation] S100A8 promoted Th1-related gene expression and S100A9 induced Th2 differentiation via activation of GATA-3 (2015)
  • Author(s): Hibino T, Miyai M, Nakajima S, Yamamoto-Tanaka M, Maeda T, Sakaguchi M, Kabashima K, Tsuboi R
  • Organizer: The 45th Annual Meeting of the European Society for Dermatological Research
  • Place of Presentation: Rotterdam, The Netherlands
  • Year and Date: 2015-09-10
  • Int'l Joint Research
• [Presentation] 表皮特異的メソトリプシンは角層剥離を制御する (2015)
  • Author(s): 宮井雅史、山西治代、松元有羽子、松浦（八谷）有宇子、柴田道男、田中（山本）真実、坪井良治、日比野利彦
  • Organizer: 第114回日本皮膚科学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2015-05-29
• [Presentation] S100A9 promotes GATA3 translocation into the nucleus via EMMPRIN and down-regulates anti-inflammatory factor, NLRP10 (2015)
  • Author(s): Hibino T, Miyai M, Sakaguchi M, Yamamoto-Tanaka M, Tsuboi R
  • Organizer: 第64回日本アレルギー学会学術大会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-27
• [Presentation] Epidermis-specific mesotrypsin is involved in corneocyte desquamation and is regulated by an intrinsic inhibitor, serpin B12 (2015)
  • Author(s): Miyai M, Yamanishi H, Matsumoto Y, Yamamoto M, Hachiya Y, Tsuboi R, Hibino T
  • Organizer: The 74th Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Atlanta, GA
  • Year and Date: 2015-05-06
  • Int'l Joint Research
• [Presentation] Atopic dermatitis susceptible gene NALP10 suppresses inflammatory reaction and NALP10 SNP mutation down-regulates NALP10 expression (2014)
  • Author(s): Miyai M, Yamamoto-Tanaka M, Inoue K, Tsuboi R, Hibino T
  • Organizer: The 39th Annual Meeting of the Japanese Society for Investigative Dermatology
  • Place of Presentation: 大阪
  • Year and Date: 2014-12-13
• [Presentation] 表皮特異的メソトリプシンは角層剥離を制御する－隠された角層剥離メカニズム－ (2014)
  • Author(s): 宮井雅史、山西治代、松元有羽子、田中(山本)真実、坪井良治、日比野利彦
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2014-11-26
• [Presentation] 表皮角化細胞の脱核には複数の経路が関与する－皮膚バリア機能形成における関与－ (2014)
  • Author(s): 田中(山本)真実, 坪井良治, 日比野利彦
  • Organizer: 第174回東京医科大学医学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-11-01
• [Presentation] S100A8/A9 promotes concomitant inflammation and proliferation via distinctive receptor oligomerization-potential relevance to atopic dermatitis (2014)
  • Author(s): Yamamoto-Tanaka M, Sakaguchi M, Miyai M, Motoyama A, Tsuboi R, Hibino T
  • Organizer: The 73rd Annual Meeting of the Society for Investigative Dermatology
  • Place of Presentation: Albuquerque, New Mexico
  • Year and Date: 2014-05-09