Elucidation of the mechanisms underlying maintaining tissue homeostasis of surface barrier at neonatal stages
| Project/Area Number |
17H04069
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Toho University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Fiscal Year 2019: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
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| Keywords | ネクロプトーシス / アポトーシス / cFLIP / 皮膚炎 / 回腸炎 / TNF / 自然リンパ球 / RIPK3 / MLKL / cFLIPs / イメージング / Reg3b / FRET / 炎症 / 上皮バリア / インターロイキン(IL)-22 / ILC3 / FasL / TRAIL / IL-6 / IL-17A / TH17細胞 / 腸炎 / インターロイキン22 |
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| Outline of Final Research Achievements |
The aim of the study is to investigate the mechanisms how enhanced epithelial cell death of the skin and small intestine induces pathological conditions in embryos or newborn mice. An increase in cell death in keratinocytes in new born mice induced interleukin 6 production, which subsequently blocked the expression of keratinocyte differentiation markers. This blockade further exacerbated skin barrier function, resulting in premature death of newborn mice.
Necroptosis of intestinal epithelial cells (IECs) in embryos induced activation of type 3 innate lymphoid cells (ILC3s), resulting in embryonic lethality along with upregulation of Reg3b, Reg3g, and Il22 expressions. Activation of innate immunity did not appear to be suppressed in the intestine of embryos due to immaturity of acquired immunity. Thus, aberrantly activated ILC3s induced IL-22 production, which subsequently induced massive apoptosis of IECs and embryonic lethality.
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| Academic Significance and Societal Importance of the Research Achievements |
細胞死の亢進したマウスモデルを解析し、乳児期のバリア障害には獲得免疫系のT細胞が中心的な役割を果たしているのではなく、自然免疫の活性化により産生される炎症性サイトカインが表皮分化マーカーの発現を強く抑制し、さらなる表皮バリア障害をもたらしていることが示された。一方で胎児期における回腸炎モデルでは、この時期に十分に獲得免疫系の細胞が成熟していないために、自然免疫系細胞の暴走を抑制することができずに、重篤な腸炎が発症することが明らかとなった。今後はこの知見をヒトに応用することで、新生児期に見られる壊死性腸炎や胎児期に見られる皮膚炎などの病態の解明や、新たな治療法の開発に繋がると考えられた。
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Report
(4 results)
Research Products
(87 results)
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[Journal Article] Necroptosis of intestinal epithelial cells induces type 3 innate lymphoid cell-dependent lethal ileitis.2019
Author(s)
Shindo R, Ohmuraya M, Komazawa-Sakon S, Miyake S, Deguchi Y, Yamazaki S, Nishina T, Yoshimoto T, Kakuta S, Koike M, Uchiyama Y, Konishi H, Kiyama H, Mikami T, Moriwaki K, Araki K, Nakano H.
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Journal Title
iScience
Volume: 15
Pages: 536-551
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Necroptosis of Intestinal Epithelial Cells Induces Type 3 Innate Lymphoid Cell-Dependent Lethal Ileitis2019
Author(s)
Shindo, R. Ohmuraya, M. Komazawa-Sakon, S. Miyake, S. Deguchi, Y. Yamazaki, S. Nishina, T. Yoshimoto, T. Kakuta, S. Koike, M. Uchiyama, Y. Konishi, H. Kiyama, H. Mikami, T. Moriwaki, K. Araki, K. Nakano, H.
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Journal Title
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A FRET biosensor for necroptosis uncovers two different modes of the release of DAMPs.2018
Author(s)
Murai S, Yamaguchi Y, Shirasaki Y, Yamagishi M, Shindo R, Hildebrand JM, Miura R, Nakabayashi O, Totsuka M, Tomida T, Adachi-Akahane S, Uemura S, Silke J, Yagita H, Miura M, Nakano H
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Journal Title
Nat Commun
Volume: 9
Issue: 1
Pages: 4457-4457
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Generation of and characterization of anti-IL-11 antibodies using newly established Il11-deficient mice.2018
Author(s)
Deguchi Y, Nishina T, Asano K, Ohmuraya M, Nakagawa Y, Nakagata N, Sakuma T, Yamamoto T, Araki K, Mikami T, Tanaka M, Nakano H.
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Journal Title
Biochemical Biophysical Research Communications
Volume: 505
Issue: 2
Pages: 453-459
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] FRETバイオセンサーによるネクロプトーシス実行の１細胞イメージング2018
Author(s)
村井 晋, 山口 良文, 白崎 義隆, 進藤 綾大, 中林 修, Hildebrand Joanne, 冨田 太一郎, 赤羽 悟美, Silke John, 三浦 正幸, 中野 裕康
Organizer
第91回日本生化学会大会
Related Report
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