期刊
DIGESTIVE DISEASES AND SCIENCES
卷 57, 期 1, 页码 38-47出版社
SPRINGER
DOI: 10.1007/s10620-011-1847-z
关键词
Celiac disease; Dendritic cells; Toll-like receptors; Intestinal permeability; HCD4/HLA-DQ8 transgenic mice
资金
- Canadian Association of Gastroenterology (CAG)/Canadian Institute of Health Research (CIHR) [GN2-114709]
- Canadian Celiac Association
- National Institute of Health [R01 DK048373-13, AGL2008-01440/ALI]
- Ministry of Science and Innovation (Spain) [CSD2007-00063]
- McMaster University Department of Medicine
- [R01 DK71003]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK071003, R01DK048373] Funding Source: NIH RePORTER
We investigated whether treatment with gliadin induces a paracellular permeability defect that enhances bacterial translocation to mesenteric lymph nodes (MLN) via resident dendritic cells (DC) expressing TLR-2 or 4 in HCD4/HLA-DQ8 transgenic mice. HLA-DQ8 transgenic mice were sensitized and subsequently gavaged with gliadin, in the presence or absence of AT1001 (paracellular permeability inhibitor). Non-sensitized mice were gavaged with indomethacin (permeability inducer) or rice cereal. CD11c and CD103 (DC markers) and TLR-2 and 4 were investigated by immunostaining. Intestinal permeability was assessed by paracellular flux of (51)Cr-EDTA in Ussing chambers. Bacterial translocation to MLN was performed by plate counting on aerobic and anaerobic conditions. In gliadin-treated mice, both (51)Cr-EDTA flux in jejunal mucosa and aerobic and anaerobic bacterial counts in MLN were increased (p < 0.05) compared to indomethacin-treated mice and controls. The inhibitor AT1001 normalized (51)Cr-EDTA flux, but had no effect on bacterial translocation in gliadin-treated mice. In addition, changes in mucosal DC marker distribution such as increased (p < 0.05) trans-epithelial CD103(+) cells and reduction (p < 0.05) of CD11c immunostaining were detected in gliadin-treated mice. Moreover, changes in DC markers and TLR-2 or 4 immunophenotypes were not associated. Pharmacological restoration of paracellular permeability was not sufficient to prevent bacterial translocation in gluten-sensitive mice. We hypothesize that transcellular mechanisms involving CD103(+)DC and CD11c(+)DC may explain in gluten-sensitive HCD4/HLA-DQ8 transgenic mice the sustained increased bacterial translocation observed in the absence of a significant inflammatory response.
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