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Updated: Mar 11, 2026
Author Spotlight: Studying the Epithelial Effects of Intestinal Inflammation In Vitro on Established Murine Colonoids
Published on: June 2, 2023
A Novel Role of Spred2 in the Colonic Epithelial Cell Homeostasis and Inflammation
Sakuma Takahashi1,2, Teizo Yoshimura2, Takahiro Ohkura2
1Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, 700-8558, Japan.
Abstract:
Rapid and adequate mucosal healing is important for a remission of ulcerative colitis (UC) patients. Here, we examined whether Spred2, a member of the Sprouty-related EVH1-domain-containing proteins that inhibit the Ras/Raf/ERK pathway, plays a role in colonic mucosal homeostasis and inflammation by using Spred2 knockout (KO) mice. We first detected increased epithelial cell proliferation and cadherin 1 expression in the colon of naïve Spred2 KO mice compared to wild-type mice. Interestingly, Spred2 KO mice were resistant to dextran sulfate sodium (DSS)-induced acute colitis as indicated by lower levels of body weight loss and disease activity index. Histologically, epithelial cell injury and inflammation were milder in the colonic mucosa of Spred2 KO mice on day 3 and almost undetectable by day 8. Experiments with bone chimeric mice indicated that Spred2-deficiency in non-hematopoietic cells was responsible for the reduced sensitivity to DSS. Finally, Spred2 KO mice developed significantly fewer tumors in response to azoxymethane plus DSS. Taken together, our results demonstrate, for the first time, that Spred2 plays an important role in the regulation of colonic epithelial cell proliferation and inflammation by potentially down-regulating the activation of ERK. Thus, Spred2 may be a new therapeutic target for the treatment of UC.
Insights
Spred2 deficiency protects against colitis and reduces tumor formation in mice by regulating colonic epithelial cell proliferation and inflammation. This suggests Spred2 as a potential therapeutic target for ulcerative colitis (UC).
Area of Science:
- Gastroenterology
- Immunology
- Molecular Biology
Background:
- Ulcerative colitis (UC) requires rapid mucosal healing for remission.
- Spred2, an inhibitor of the Ras/Raf/ERK pathway, is implicated in cellular processes.
- The role of Spred2 in colonic mucosal homeostasis and inflammation is not well understood.
Purpose of the Study:
- To investigate the role of Spred2 in colonic mucosal homeostasis and inflammation.
- To determine if Spred2 deficiency impacts dextran sulfate sodium (DSS)-induced colitis and tumor development.
Main Methods:
- Utilized Spred2 knockout (KO) mice and wild-type littermates.
- Induced acute colitis using dextran sulfate sodium (DSS).
- Assessed epithelial cell proliferation, inflammation, and tumor formation.
Main Results:
- Spred2 KO mice exhibited increased epithelial cell proliferation and cadherin 1 expression in the colon.
- Spred2 KO mice showed resistance to DSS-induced colitis, with reduced weight loss and inflammation.
- Spred2 deficiency in non-hematopoietic cells mediated the reduced sensitivity to DSS.
- Spred2 KO mice developed fewer tumors in response to azoxymethane plus DSS treatment.
Conclusions:
- Spred2 plays a crucial role in regulating colonic epithelial cell proliferation and inflammation.
- Spred2 deficiency confers protection against colitis and reduces tumorigenesis.
- Spred2 represents a potential therapeutic target for ulcerative colitis (UC).
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