Analysis of the IFN-1 and autophagy mediated pathogenesis in inflammatory bowel disease

• Project/Area Number: 20K22895
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Ito Go 東京医科歯科大学, 高等研究院, プロジェクト助教 (20733900)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: IFN-1 / Atg16L1 / アポトーシス / ネクロプトーシス / RIP1キナーゼ / RIP1 / autophagy / apoptosis / necroptosis / IBD

Outline of Research at the Start

炎症性腸疾患には潰瘍性大腸炎・クローン病の2疾患が存在するが、いずれも消化管に慢性炎症と難治性潰瘍を起こす難病である。炎症性腸疾患の発症・再燃因子の一つとしてウィルス感染等を契機とした免疫応答が知られている。同応答にはI型インターフェロン(IFN-1)が中心的な役割を担うが、炎症性腸疾患の病態において「腸上皮」におけるIFN-1応答の意義・役割の詳細は明らかでない。本研究では腸上皮における蛋白分解過程の一つである「オートファジー」と「細胞死」を介して局所炎症の惹起・遷延に繋がる新規IFN-1応答に焦点を当て、その分子機構の全貌を明らかにする。

Outline of Final Research Achievements

We found that IFN-1 induces cell death in intestinal epithelial cells and that this effect is significantly accelerated in Atg16L1-deficient intestinal epithelium. In addition, inactivation of RIP1 kinase, one of the key molecules in the regulation of cell death, confers resistance to IFN-1-induced cell death and suppresses the cell death-enhancing effect in Atg16L1-deficient intestinal epithelium. The IFN-1 response is enhanced and promoted in an environment where intracellular autophagy is impaired, suggesting that the IFN-1-autophagy interaction in the intestinal epithelium plays an important role in the pathogenesis of inflammatory bowel disease and that RIP1 kinase activity may play an central role in this interaction. RIP1 kinase activity may play an important role in the pathogenesis of inflammatory bowel disease.

Academic Significance and Societal Importance of the Research Achievements

ウイルス感染は炎症性腸疾患の再燃・増悪因子の一つである。ウイルス感染によりIFN-1は分泌されることが知られている。今回我々は腸上皮における炎症性腸疾患の責任遺伝子であるオートファジー関連遺伝子Atg16L1とRIP1キナーゼが制御する細胞死を介して局所炎症の惹起・遷延に繋がる新規IFN-1応答を明らかとした。以上のことにより「感染による炎症性腸疾患の炎症増悪、遷延に対する新規治療の開発」「新規オートファージー関連細胞死のメカニズムの解明」につながることが期待される。

Research Products

• [Journal Article] Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease (2021)
  • Author(s): Zheng T, Ito G, Franke A et al.
  • Journal Title: Gut Volume: 70(8) Issue: 8 Pages: 1538-1549
  • DOI: 10.1136/gutjnl-2020-323868
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Cellular "Hub" Function to Resolve Colitis. (2021)
  • Author(s): Ito G, Yui S, Okamoto R.
  • Journal Title: Cell Mol Gastroenterol Hepatol Volume: 12(2) Issue: 2 Pages: 789-790
  • DOI: 10.1016/j.jcmgh.2021.04.008
  • Peer Reviewed
• [Journal Article] Functional analysis of isoflavones using patient-derived human colonic organoids (2021)
  • Author(s): Tsuchiya Mao、Ito Go、Hama Minami、Nagata Sayaka、Kawamoto Ami、Suzuki Kohei、Shimizu Hiromichi、Anzai Sho、Takahashi Junichi、Kuno Reiko、Takeoka Sayaka、Hiraguri Yui、Sugihara Hady Yuki、Mizutani Tomohiro、Yui Shiro、Oshima Shigeru、Tsuchiya Kiichiro、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 542 Pages: 40-47
  • DOI: 10.1016/j.bbrc.2021.01.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Notch and TNF-α signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients (2021)
  • Author(s): Kuno Reiko、Ito Go、Kawamoto Ami、Hiraguri Yui、Sugihara Hady Yuki、Takeoka Sayaka、Nagata Sayaka、Takahashi Junichi、Tsuchiya Mao、Anzai Sho、Mizutani Tomohiro、Shimizu Hiromichi、Yui Shiro、Oshima Shigeru、Tsuchiya Kiichiro、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Biochemistry and Biophysics Reports Volume: 25 Pages: 100906-100906
  • DOI: 10.1016/j.bbrep.2020.100906
  • Peer Reviewed / Open Access / Int'l Joint Research