Immune response for endoplasmic reticulum stress on intestinal inflammation

• Project/Area Number: 16K19162
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: Osaka City University
• Principal Investigator: HOSOMI Shuhei 大阪市立大学, 大学院医学研究科, 講師 (60554938)
• Research Collaborator: Richard Blumberg S. Brigham and Women's Hospital ; Sugita Naoko 大阪市立大学, 大学院医学研究科 消化器内科学
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 小胞体ストレス / Xbp1 / NKG2D / IgA / 肥満細胞 / 炎症性腸疾患 / MULT1 / クローン病 / 自然免疫 / 腸管上皮細胞間リンパ球 / 樹状細胞

Outline of Final Research Achievements

Endoplasmic reticulum (ER) stress in intestinal epithelial cells (IEC), which can be induced by IEC-specific deletion of Xbp1 (Xbp1ΔIEC) , an unfolded protein response-related transcription factor, develops spontaneous inflammation of the small intestine. Xbp1ΔIEC is shown to cause increased expression of MULT1 on of natural killer group 2 member D (NKG2D) ligands, associating with increased numbers of intraepithelial NKG2D-expressing group 1 innate lymphoid cells (ILC1). Blockade of NKG2D suppresses cytolysis against ER-stressed epithelial cells in vitro and spontaneous enteritis in vivo. Pharmacological depletion of NK1.1+ cells also significantly improved enteritis. IEC ER stress also induces a polyreactive IgA response via T cell independent and microbiota independent pathway, which is protective against gut inflammation. On the other hand, ER stress on mast cells can induce TNF and Amphiregulin via ER stress-elated transcription factor ATF4.

Academic Significance and Societal Importance of the Research Achievements

多因子疾患と考えられている炎症性腸疾患（クローン病や潰瘍性大腸炎）の病因の一つとして、小胞体（ER）ストレスによって誘導されるNKG2D-NKG2Dリガンドを介した炎症が明らかとなったことは、炎症性腸疾患治療薬の新規治療標的となりうることが期待される結果である。さらに、腸管ERストレスが腸管保護的に作用するIgAを誘導するこが証明されたことは、過剰なERストレスによって悪化しうる腸内環境を維持するための、新しい腸管恒常性維持機能の発見となった。

Research Products

• [Int'l Joint Research] Harvard Medical School/Brigham and Women's Hospital(米国)
• [Journal Article] Epithelial endoplasmic reticulum stress orchestrates a protective IgA response (2019)
  • Author(s): Grootjans J, Krupka N, Hosomi S, Matute JD, Hanley T, Saveljeva S, Gensollen T, Heijmans J, Li H, Limenitakis JP, Ganal-Vonarburg SC, Suo S, Luoma AM, Shimodaira Y, Duan J, Shih DQ, Conner ME, Glickman JN, Fuhler GM, Palm NW, de Zoete MR, van der Woude CJ, Yuan GC, Targan SR, Macpherson AJ, Kaser A, Blumberg RS
  • Journal Title: Science Volume: 363 Issue: 6430 Pages: 993-998
  • DOI: 10.1126/science.aat7186
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] New Insights Into the Regulation of Natural-Killer Group 2 Member D (NKG2D) and NKG2D-Ligands: Endoplasmic Reticulum Stress and CEA-Related Cell Adhesion Molecule 1 (2018)
  • Author(s): Hosomi Shuhei、Grootjans Joep、Huang Yu-Hwa、Kaser Arthur、Blumberg Richard S.
  • Journal Title: Frontiers in Immunology Volume: 9 Pages: 1324-1324
  • DOI: 10.3389/fimmu.2018.01324
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation (2017)
  • Author(s): Hosomi Shuhei、Grootjans Joep、Tschurtschenthaler Markus、Krupka Niklas、Matute Juan D.、Flak Magdalena B.、Martinez-Naves Eduardo、Gomez del Moral Manuel、Glickman Jonathan N.、Ohira Mizuki、Lanier Lewis L.、Kaser Arthur、Blumberg Richard
  • Journal Title: The Journal of Experimental Medicine Volume: 214 Issue: 10 Pages: 2985-2997
  • DOI: 10.1084/jem.20162041
  • Peer Reviewed / Open Access
• [Presentation] 小胞体ストレス応答による (2017)
  • Author(s): 細見 周平、杉田 奈央子、大谷 恒史、 山上 博一、谷川 徹也、渡辺 俊雄、藤原 靖弘
  • Organizer: 日本消化器免疫学会総会