Functional genomic analysis of skin disorders with alarmin activation

• Project/Area Number: 17K10219
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Dermatology
• Research Institution: Hyogo Medical University
• Principal Investigator: Yamanishi Kiyofumi 兵庫医科大学, 医学部, 教授 (10182586)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: アラーミン / 角化症 / アトピー性皮膚炎 / 遺伝子変異 / 病態モデルマウス / IL-33 / トランスグルタミナーゼ / 皮膚炎 / 魚鱗癬 / 免疫不全症 / 変異 / 遺伝子 / ゲノム / 皮膚科学 / 生体分子 / 微生物叢

Outline of Final Research Achievements

Causative mutations were identified in 16 cases of patients with ichthyosis (5 cases), palmoplantar keratoderma (14 cases) and inflammatory keratinization disorder (2 cases). Defects in nuclear localization of NFKB2 in the epidermal keratinocytes were found in a case with NFKB2 mutation, and the up-regulated calprotectin in the epidermis was observed in cases with ABCA12, NIPAL4 or SLURP1 mutation. RNA Seq revealed the expression of the fetuin genes, a novel alarmin, in the epidermis of Tgm1 knockout mice. Furthermore, atopic dermatitis induced by IL-33 overexpression in the skin is demonstrated to be dependent on type 2 innate lymphoid cells and is also mediated by basophils. Thus, alarmins in the epidermis are possibly involved in various pathological conditions of the skin.

Academic Significance and Societal Importance of the Research Achievements

外界からのさまざまな侵襲や皮膚のバリア障害によって表皮がストレスに曝されると、角化細胞から複数の警告因子（アラーミン）が放出され、生理的な修復反応や自然免疫系の炎症反応が誘導される。本研究では角化症およびアトピー性皮膚炎等を研究対象として、皮膚におけるアラミーンの発現と病態についてRNA-seq等を用いて機能ゲノム学的に解析した。その結果、皮膚におけるカルプロテクチン、フェチュイン、インターロイキン３３等のアラーミンの活性化が持続すると皮膚の恒常性維持が困難になり、表皮の肥厚、角層増生、皮膚炎等の病的状態を誘導し、難治性皮膚疾患の病態形成に至ることが示唆された。

Research Products

• [Int'l Joint Research] Korea University College of Medicine(韓国)
• [Journal Article] IL-33-induced atopic dermatitis-like inflammation in mice is mediated by group 2 innate lymphoid cells in concert with basophils (2019)
  • Author(s): Imai Y, Yasuda K, Nagai M, Kusakabe M, Kubo M, Nakanishi K, Yamanishi K
  • Journal Title: J Invest Dermatol Volume: 139 Issue: 10 Pages: 2185-2194
  • DOI: 10.1016/j.jid.2019.04.016
  • Peer Reviewed
• [Journal Article] Japanese case of Mal de Meleda with a novel missense mutation of p.Thr52Ala in the second protruding finger of secreted Ly‐6/uPAR‐related protein 1 (2019)
  • Author(s): Kunisada Makoto、Yamanishi Kiyofumi、Nishigori Chikako
  • Journal Title: The Journal of Dermatology Volume: 46 Issue: 7
  • DOI: 10.1111/1346-8138.14781
  • Peer Reviewed / Open Access
• [Journal Article] Japanese case of Bothnian-type palmoplantar keratoderma with a novel missense mutation of p.Trp35Ser in extracellular loop A of aquaporin-5 (2019)
  • Author(s): Wada Yoshihiro、Kusakabe Minori、Nagai Makoto、Imai Yasutomo、Yamanishi Kiyofumi
  • Journal Title: The Journal of Dermatology Volume: 46 Issue: 3
  • DOI: 10.1111/1346-8138.14621
  • Peer Reviewed
• [Journal Article] Psoriasiform dermatitis associated with common variable immunodeficiency 10 due to an Arg853* mutation in the NFKB2 gene (2019)
  • Author(s): Nagai Makoto、Imai Yasutomo、Yamanishi Kiyofumi
  • Journal Title: The Journal of Dermatology Volume: 46 Issue: 1
  • DOI: 10.1111/1346-8138.14524
  • Peer Reviewed
• [Journal Article] IL-33 down-regulates CLDN1 expression through the ERK/STAT3 pathway in keratinocytes (2018)
  • Author(s): Ryu Woo-In、Lee Hana、Bae Hyun Cheol、Jeon Jiehyun、Ryu Hwa Jung、Kim Jaehyung、Kim Ji Hyun、Son Ji Won、Kim JaeYoung、Imai Yasutomo、Yamanishi Kiyofumi、Jeong Sang Hoon、Son Sang Wook
  • Journal Title: J Dermatol Sci Volume: － Issue: 3 Pages: 313-322
  • DOI: 10.1016/j.jdermsci.2018.02.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Mild case of congenital ichthyosiform erythroderma with periodic exacerbation: Novel mutations in ABCA12 and upregulation of calprotectin in the epidermis. (2017)
  • Author(s): Wada Y, Kusakabe M, Nagai M, Yamamoto M, Imai Y, Ide YH, Hirota S, Yamanishi K.
  • Journal Title: J Dermatol. Volume: 44 Issue: 11
  • DOI: 10.1111/1346-8138.13976
  • Peer Reviewed
• [Journal Article] Case of harlequin ichthyosis with a favorable outcome: Early treatment and novel, differentially expressed, alternatively spliced transcripts of the ATP-binding cassette subfamily A member 12 gene. (2017)
  • Author(s): Washio K, Sumi M, Nakata K, Fukunaga A, Yamana K, Koda T, Morioka I, Nishigori C, Yamanishi.
  • Journal Title: Journal of Dermatology Volume: 印刷中 Issue: 8 Pages: 950-953
  • DOI: 10.1111/1346-8138.13823
  • Peer Reviewed
• [Presentation] 乾癬様皮疹を伴ったNFKB2遺伝子変異による分類不能型免疫不全症の１例 (2018)
  • Author(s): 永井諒、今井康友、山西清文
  • Organizer: 第117回日本皮膚科学会総会
• [Presentation] 新生児の紅皮症 (2018)
  • Author(s): 山西清文
  • Organizer: 第117回日本皮膚科学会総会
  • Invited