2018 Fiscal Year Final Research Report
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
|
| Keywords | 小胞体ストレス / Xbp1 / NKG2D / IgA / 肥満細胞 |
|---|
| 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.
|
| Free Research Field |
消化器内科
|
| 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。
|
