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Gut Epithelial Vitamin D Receptor Regulates Microbiota-Dependent Mucosal Inflammation by Suppressing Intestinal Epithelial Cell Apoptosis
- Source :
- Endocrinology. 159(2)
- Publication Year :
- 2017
-
Abstract
- Recent studies show that colonic vitamin D receptor (VDR) signaling protects the mucosal epithelial barrier and suppresses colonic inflammation, but the underlying molecular mechanism remains to be fully understood. To investigate the implication of colonic VDR downregulation seen in patients with inflammatory bowel disease, we assessed the effect of gut epithelial VDR deletion on colonic inflammatory responses in an experimental colitis model. In a 2,4,6-trinitrobenzenesulfonic acid-induced colitis model, mice carrying VDR deletion in gut epithelial cells [VDRflox/flox (VDRf/f);Villin-Cre or VDRΔIEC] or in colonic epithelial cells (VDRf/f;CDX2-Cre or VDRΔCEC) developed more severe clinical colitis than VDRf/f control mice, characterized by more robust T-helper (TH)1 and TH17 responses, with greater increases in mucosal interferon (IFN)-γ+, interleukin (IL)-17+, and IFN-γ+IL-17+ T cells. Accompanying the severe mucosal inflammation was more profound colonic epithelial cell apoptosis in the mutant mice. Treatment with caspase inhibitor Q-VD-OPh dramatically reduced colitis severity and attenuated TH1 and TH17 responses in VDRΔCEC mice. The blockade of cell apoptosis also prevented the increase in mucosal CD11b+CD103+ dendritic cells (DCs), known to be critical for TH17-cell activation. Moreover, depletion of gut commensal bacteria with antibiotics eliminated the robust TH1 and TH17 responses and CD11b+CD103+ DC induction. Taken together, these observations demonstrate that gut epithelial VDR deletion aggravates epithelial cell apoptosis, resulting in increases in mucosal barrier permeability. Consequently, invading luminal bacteria activate CD11b+CD103+ DCs, which promote mucosal TH1 and TH17 responses. Therefore, gut epithelial VDR signaling controls mucosal inflammation by suppressing epithelial cell apoptosis.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Colon
Inflammation
Apoptosis
Mice, Transgenic
Calcitriol receptor
Inflammatory bowel disease
03 medical and health sciences
Mice
0302 clinical medicine
Endocrinology
Downregulation and upregulation
Intestinal mucosa
Interferon
Internal medicine
medicine
Animals
Colitis
Intestinal Mucosa
Research Articles
Chemistry
Microbiota
Epithelial Cells
medicine.disease
Inflammatory Bowel Diseases
Intestines
030104 developmental biology
Cancer research
Receptors, Calcitriol
030211 gastroenterology & hepatology
medicine.symptom
medicine.drug
Subjects
Details
- ISSN :
- 19457170
- Volume :
- 159
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Endocrinology
- Accession number :
- edsair.doi.dedup.....1c393ded35be8d547c2452e55ac0cd79