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TLR1-induced chemokine production is critical for mucosal immunity against Yersinia enterocolitica.

Sugiura Y, Kamdar K, Khakpour S, Young G, Karpus WJ, DePaolo RW - Mucosal Immunol (2013)

Bottom Line: Intestinal epithelial cells are a central player in barrier function and also in communicating signals from invading pathogens to the underlying immune tissue.Here we demonstrate that activation of Toll-like receptor 1 (TLR1) in the epithelium leads to the upregulation of the chemokine CCL20 during oral infection with Yersinia enterocolitica.These data demonstrate a novel role for TLR1 signaling in the intestinal epithelium and demonstrate that together TLR1 and CCL20 are critical mediators of TH17 immunity through the activation and recruitment of DCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Midwestern University, Downers Grove, Illinois, USA.

ABSTRACT
Our gastrointestinal tract is a portal of entry for a number of bacteria and viruses. Thus, this tissue must develop ways to induce antigen-specific T cell and antibody responses quickly. Intestinal epithelial cells are a central player in barrier function and also in communicating signals from invading pathogens to the underlying immune tissue. Here we demonstrate that activation of Toll-like receptor 1 (TLR1) in the epithelium leads to the upregulation of the chemokine CCL20 during oral infection with Yersinia enterocolitica. Further, both neutralization of CCL20 using polyclonal antibody treatment and deletion of TLR1 resulted in a defect in CCR6+ dendritic cells (DCs), which produce innate cytokines that help to induce anti-Yersinia-specific T helper 17 (TH17) cells and IgA production. These data demonstrate a novel role for TLR1 signaling in the intestinal epithelium and demonstrate that together TLR1 and CCL20 are critical mediators of TH17 immunity through the activation and recruitment of DCs.

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CCL20 is important for survival and clearance of Y. enterocolitica. (a) Survival of mice fed 1 × 105 c.f.u. (colony-forming unit) Y. enterocolitica and treated with anti-CCL2 or anti-IgG polyclonal serum every other day for 10 days. N=10 mice per group; *P=0.0132 (Wilcoxon Log-Rank test). (b) Bacterial burden in the mesenteric lymph node 3 days post infection. Data are pooled from two independent experiments (n=5 mice per group). **P<0.01 (Student's paired t-test).
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fig3: CCL20 is important for survival and clearance of Y. enterocolitica. (a) Survival of mice fed 1 × 105 c.f.u. (colony-forming unit) Y. enterocolitica and treated with anti-CCL2 or anti-IgG polyclonal serum every other day for 10 days. N=10 mice per group; *P=0.0132 (Wilcoxon Log-Rank test). (b) Bacterial burden in the mesenteric lymph node 3 days post infection. Data are pooled from two independent experiments (n=5 mice per group). **P<0.01 (Student's paired t-test).

Mentions: Stimulation of IECs and FAE by bacteria has been shown to induce the secretion of CCL2010, 38 and attract CCR6+ cells.11 This interaction has been shown to be important for the generation of pathogen-specific T cells.20 Previously, we have shown that the absence of TLR1 signaling increases the mortality and bacterial burden after oral infection by Y. enterocolitica.23 Here, we wanted to investigate whether the induction of CCL20 would similarly impact the pathogenesis of mucosal Y. enterocolitica infection. Using a polyclonal neutralizing antibody against CCL20,18 we treated wild-type mice every other day after oral infection with Y. enterocolitica. Compared with control-treated mice, mice receiving the neutralizing antibody against CCL20 had a more severe disease phenotype, as evidenced by a higher mortality (Figure 3a) and a 10-fold higher bacterial burden in the MLN 3 days following oral infection (Figure 3b).


TLR1-induced chemokine production is critical for mucosal immunity against Yersinia enterocolitica.

Sugiura Y, Kamdar K, Khakpour S, Young G, Karpus WJ, DePaolo RW - Mucosal Immunol (2013)

CCL20 is important for survival and clearance of Y. enterocolitica. (a) Survival of mice fed 1 × 105 c.f.u. (colony-forming unit) Y. enterocolitica and treated with anti-CCL2 or anti-IgG polyclonal serum every other day for 10 days. N=10 mice per group; *P=0.0132 (Wilcoxon Log-Rank test). (b) Bacterial burden in the mesenteric lymph node 3 days post infection. Data are pooled from two independent experiments (n=5 mice per group). **P<0.01 (Student's paired t-test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3760963&req=5

fig3: CCL20 is important for survival and clearance of Y. enterocolitica. (a) Survival of mice fed 1 × 105 c.f.u. (colony-forming unit) Y. enterocolitica and treated with anti-CCL2 or anti-IgG polyclonal serum every other day for 10 days. N=10 mice per group; *P=0.0132 (Wilcoxon Log-Rank test). (b) Bacterial burden in the mesenteric lymph node 3 days post infection. Data are pooled from two independent experiments (n=5 mice per group). **P<0.01 (Student's paired t-test).
Mentions: Stimulation of IECs and FAE by bacteria has been shown to induce the secretion of CCL2010, 38 and attract CCR6+ cells.11 This interaction has been shown to be important for the generation of pathogen-specific T cells.20 Previously, we have shown that the absence of TLR1 signaling increases the mortality and bacterial burden after oral infection by Y. enterocolitica.23 Here, we wanted to investigate whether the induction of CCL20 would similarly impact the pathogenesis of mucosal Y. enterocolitica infection. Using a polyclonal neutralizing antibody against CCL20,18 we treated wild-type mice every other day after oral infection with Y. enterocolitica. Compared with control-treated mice, mice receiving the neutralizing antibody against CCL20 had a more severe disease phenotype, as evidenced by a higher mortality (Figure 3a) and a 10-fold higher bacterial burden in the MLN 3 days following oral infection (Figure 3b).

Bottom Line: Intestinal epithelial cells are a central player in barrier function and also in communicating signals from invading pathogens to the underlying immune tissue.Here we demonstrate that activation of Toll-like receptor 1 (TLR1) in the epithelium leads to the upregulation of the chemokine CCL20 during oral infection with Yersinia enterocolitica.These data demonstrate a novel role for TLR1 signaling in the intestinal epithelium and demonstrate that together TLR1 and CCL20 are critical mediators of TH17 immunity through the activation and recruitment of DCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Midwestern University, Downers Grove, Illinois, USA.

ABSTRACT
Our gastrointestinal tract is a portal of entry for a number of bacteria and viruses. Thus, this tissue must develop ways to induce antigen-specific T cell and antibody responses quickly. Intestinal epithelial cells are a central player in barrier function and also in communicating signals from invading pathogens to the underlying immune tissue. Here we demonstrate that activation of Toll-like receptor 1 (TLR1) in the epithelium leads to the upregulation of the chemokine CCL20 during oral infection with Yersinia enterocolitica. Further, both neutralization of CCL20 using polyclonal antibody treatment and deletion of TLR1 resulted in a defect in CCR6+ dendritic cells (DCs), which produce innate cytokines that help to induce anti-Yersinia-specific T helper 17 (TH17) cells and IgA production. These data demonstrate a novel role for TLR1 signaling in the intestinal epithelium and demonstrate that together TLR1 and CCL20 are critical mediators of TH17 immunity through the activation and recruitment of DCs.

Show MeSH
Related in: MedlinePlus