Abstract
Cross-talk between different components of the intestinal barrier and the immune system may be important in maintaining gut homeostasis. A crucial part of the gut barrier is the mucus layer, a cross-linked gel on top of the intestinal epithelium that consists predominantly of the mucin glycoprotein MUC2. However, whether the mucin layer actively regulates intestinal immune cell responses is not clear. Because recent evidence suggests that intestinal dendritic cells (DCs) may be regulated by the mucus layer, we purified intestinal mucin, incubated it with human DCs, and determined the functional effects. Here we show that expression of the chemokine IL-8 and co-stimulatory DC markers CD86 and CD83 are significantly up-regulated on human DCs in the presence of intestinal mucins. Additionally, mucin-exposed DCs promoted neutrophil migration in an IL-8–dependent manner. The stimulatory effects of mucins on DCs were not due to mucin sample contaminants such as lipopolysaccharide, DNA, or contaminant proteins. Instead, mucin glycans are important for the pro-inflammatory effects on DCs. Thus, intestinal mucins are capable of inducing important pro-inflammatory functions in DCs, which could be important in driving inflammatory responses upon intestinal barrier damage.
Highlights
Cross-talk between different components of the intestinal barrier and the immune system may be important in maintaining gut homeostasis
The phenotype of human monocyte-derived DCs (moDCs) was confirmed by flow cytometry, with cells showing a lack of CD14 expression and reduced expression of CD33 compared with monocytes and high expression of the dendritic cells (DCs)-associated markers HLA-DR, CD11c, CD1c, CD11b, CD141, and CD13 (Fig. S1)
Changes in moDC gene expression after incubation with a preparation enriched in human MUC2 were analyzed using a DC PCR array, which analyses expression of 84 genes related to DC and antigen presenting cell function
Summary
Induced activation of human DCs, showing enhanced expression of the co-stimulatory molecules CD83 and CD86, and enhanced production of the pro-inflammatory chemokine IL-8. Such activation was not a result of bacterial or protein contaminants but instead depended on glycosylation of the mucin. DCs were able to promote neutrophil migration in an IL-8 – dependent fashion. Our results suggest that mucins can have pro-inflammatory properties on DCs, which may be important in regulation of intestinal immune responses during homeostasis and barrier disruption
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