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CXCR4 antagonist AMD3100 attenuates colonic damage in mice with experimental colitis
Xian-Ming Xia1, Fang-Yu Wang, Wen-An Xu
1Department of Gastroenterology and Hepatology, Jinling Hospital, Nanjing 210002, Jiangsu Province, China.
Aim:
To investigate the effects of the chemokine stromal cell-derived factor-1 (CXCL12) receptor (CXCR4) antagonist AMD3100 on colonic inflammation and epithelial barrier in dextran sulfate sodium (DSS)-induced colitis in mice.
Methods:
Experimental colitis was induced by administration of 5% DSS for 7 d, and assays performed on intestinal segments from the ileocecal valve to the anus. Colonic morphology was examined by hematoxylin and eosin staining. Colonic cytokines were determined by enzyme-linked immunosorbent assay. Myeloperoxidase (MPO) activity (indicator of inflammatory infiltration) was observed spectrophotometrically. Gut permeability was assessed by mucosal-to-serosal clearance of fluorescein isothiocyanate-conjugated dextran 4000 (FD4) in everted gut sacs. The apoptosis of colonic epithelium was assessed by Hoechst-33342 staining. To further elucidate the role of CXCR4 in colonic inflammation, we also investigated the effect of AMD3100 on migration and cytokine production of isolated peripheral blood mononuclear cells (PBMCs).
Results:
DSS-induced colitis was characterized by morphologic changes, as well as increased colonic cytokines, inflammatory infiltration, epithelial apoptosis, and intestinal permeability in mice. In AMD3100-treated mice, epithelial destruction, inflammatory infiltration, and submucosal edema were markedly reduced; colonic tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) levels, as well as MPO activity were significantly decreased. Increased intestinal permeability in DSS-treated mice was significantly reduced by AMD3100. The number of apoptotic cells in colitis mice was markedly increased after DSS administration, and decreased when treated with the CXCR4 antagonist AMD3100. In pre-activated PBMCs, CXCL12 stimulation significantly increased the migration of PBMCs, and was inhibited by AMD3100. Moderately increased TNF-alpha, IL-6, and IFN-gamma from CXCL12-treated PBMCs were also reduced by AMD3100.
Conclusion:
The CXCR4 antagonist AMD3100 exerts therapeutic effects on experimental colitis by inhibiting colonic inflammation and enhancing epithelial barrier integrity.
Insights
The CXCR4 antagonist AMD3100 effectively treats experimental colitis in mice by reducing inflammation and improving the gut barrier. This study shows AMD3100 inhibits inflammatory cell migration and cytokine release, offering therapeutic potential for colitis.
Area of Science:
- Gastroenterology
- Immunology
- Pharmacology
Background:
- Dextran sulfate sodium (DSS)-induced colitis is a common model for inflammatory bowel disease.
- Stromal cell-derived factor-1 (CXCL12) and its receptor CXCR4 play roles in inflammatory conditions.
- AMD3100 is a CXCR4 antagonist with potential therapeutic applications.
Purpose of the Study:
- To evaluate the therapeutic effects of AMD3100 on colonic inflammation and epithelial barrier function in a mouse model of colitis.
- To investigate the impact of AMD3100 on inflammatory cell migration and cytokine production.
Main Methods:
- Experimental colitis was induced using DSS in mice.
- Colonic tissues were analyzed for morphology, cytokines, myeloperoxidase (MPO) activity, and apoptosis.
- Gut permeability was assessed using fluorescein isothiocyanate-conjugated dextran (FD4).
- The effect of AMD3100 on peripheral blood mononuclear cell (PBMC) migration and cytokine release was examined.
Main Results:
- DSS-induced colitis showed significant inflammation, epithelial damage, increased cytokines (TNF-alpha, IL-6, IFN-gamma), MPO activity, apoptosis, and gut permeability.
- AMD3100 treatment markedly reduced these inflammatory markers and improved epithelial integrity.
- AMD3100 inhibited CXCL12-induced PBMC migration and reduced pro-inflammatory cytokine production.
Conclusions:
- AMD3100 demonstrates significant therapeutic benefits in experimental colitis.
- The CXCR4 antagonist effectively mitigates colonic inflammation and enhances epithelial barrier function.
- AMD3100 holds promise as a treatment for inflammatory bowel diseases.
