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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis
Grace Y Chen1, Michael H Shaw, Gloria Redondo
1Departments of Internal Medicine, Division of Hematology and Oncology, University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109-5938, USA.
Abstract:
There is growing evidence that the host innate immune system has a critical role in regulating carcinogenesis, but the specific receptors involved and the importance of their interaction with commensal bacteria need to be elucidated. Two major classes of innate immune receptors, the Toll-like receptors and Nod-like receptors, many of which are upstream of nuclear factor-kappaB, are involved in the detection of intestinal bacteria. The Toll-like receptors have been implicated in promoting colon tumorigenesis, but the role of Nod-like receptors in regulating tumorigenesis remains unclear. Using an established mouse model system of colitis-associated colon tumorigenesis, we show that Nod1 deficiency results in the increased development of both colitis-associated and Apc tumor suppressor-related colon tumors. In the absence of Nod1 signaling, there is a greater disruption of the intestinal epithelial cell barrier due to chemically induced injury as manifested by increased surface epithelial apoptosis early on during chemically induced colitis and increased intestinal permeability. The increased intestinal permeability is associated with enhanced inflammatory cytokine production and epithelial cell proliferation in Nod1-deficient mice as compared with wild-type mice. Depletion of the gut microbiota suppressed tumor development in Nod1-deficient mice, thus highlighting a link between the commensal bacteria within the intestine and the host innate immune Nod1 signaling pathway in the regulation inflammation-mediated colon cancer development.
Insights
Nod1 deficiency exacerbates colon tumor development by increasing intestinal permeability and inflammation. Gut bacteria depletion mitigates this effect, revealing Nod1
Area of Science:
- Immunology
- Gastroenterology
- Oncology
Background:
- The innate immune system plays a crucial role in regulating cancer development.
- Toll-like receptors (TLRs) and Nod-like receptors (NLRs) are key innate immune receptors detecting intestinal bacteria.
- The role of NLRs, specifically Nod1, in colon tumorigenesis is not well understood.
Purpose of the Study:
- To investigate the role of Nod1 signaling in colitis-associated and Apc tumor suppressor-related colon tumorigenesis.
- To elucidate the impact of Nod1 deficiency on intestinal barrier function and host-microbe interactions in colon cancer.
Main Methods:
- Utilized a mouse model of colitis-associated colon tumorigenesis.
- Assessed tumor development in Nod1-deficient versus wild-type mice.
- Analyzed intestinal epithelial barrier integrity, apoptosis, permeability, cytokine production, and epithelial cell proliferation.
- Investigated the effect of gut microbiota depletion on tumor development in Nod1-deficient mice.
Main Results:
- Nod1 deficiency significantly increased the development of both colitis-associated and Apc tumor suppressor-related colon tumors.
- Nod1-deficient mice exhibited increased epithelial apoptosis, intestinal permeability, and inflammatory cytokine production.
- Depletion of gut microbiota suppressed tumor development in Nod1-deficient mice, indicating a critical role for commensal bacteria.
Conclusions:
- Nod1 signaling is essential for maintaining intestinal barrier integrity and suppressing colon tumorigenesis.
- Nod1 deficiency promotes colon cancer development by disrupting the intestinal barrier and enhancing inflammation in a microbiota-dependent manner.
- This study highlights the intricate link between innate immunity (Nod1) and gut microbiota in regulating colon cancer.
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