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Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells

Abstract

Toll-like receptors (TLRs) recognize distinct microbial components and induce innate immune responses. TLR5 is triggered by bacterial flagellin. Here we generated Tlr5−/− 1mice and assessed TLR5 function in vivo. Unlike other TLRs, TLR5 was not expressed on conventional dendritic cells or macrophages. In contrast, TLR5 was expressed mainly on intestinal CD11c+ lamina propria cells (LPCs). CD11c+ LPCs detected pathogenic bacteria and secreted proinflammatory cytokines in a TLR5-dependent way. However, CD11c+ LPCs do not express TLR4 and did not secrete proinflammatory cytokines after exposure to a commensal bacterium. Notably, transport of pathogenic Salmonella typhimurium from the intestinal tract to mesenteric lymph nodes was impaired in Tlr5−/− mice. These data suggest that CD11c+ LPCs, via TLR5, detect and are used by pathogenic bacteria in the intestinal lumen.

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Figure 1: Macrophages and conventional DCs are hyporesponsive to flagellin.
Figure 2: Gene expression induced by flagellin stimulation in IECs.
Figure 3: TLR5 is highly expressed on CD11c+ LPCs.
Figure 4: TLR5-mediated CD11c+ LPC cytokine production.
Figure 5: Flagellin-induced gene expression in CD11c+ LPCs.
Figure 6: CD11c+ LPCs detect pathogenic bacteria via TLR5.
Figure 7: S. typhimurium uses TLR5 for systemic infection.

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Acknowledgements

We thank K. Smith and T. Hawn (Institute for Systems Biology, Seattle, Washington) for providing purified flagellin; C. Sasagawa and T. Suzuki (Institute of Medical Science, Tokyo, Japan) for providing bacteria; members of the DNA-chip Development Center for Infectious Diseases (RIMD, Osaka University, Osaka, Japan) for technical advice; N. Kitagaki for technical assistance; and M. Hashimoto for secretarial assistance. Supported by Special Coordination Funds, the Ministry of Education, Culture, Sports, Science and Technology, and Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists.

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S.U. and M.H.J. did most of the experiments to characterize mouse phenotypes; N.C. helped with the quantitative PCR, microarray analysis, isolation of cells and enzyme-linked immunosorbent assays; Z.G. helped to isolate cells and with immunostaining and did the surgical operations for the intestinal loop assay; Y.K. helped with analysis of microarray data; M.Y. helped to generate Tlr5−/− mice; H.K. helped with the enzyme-linked immunosorbent assays; N.S. helped to isolate cells; H.M. provided S. typhimurium and provided instructions for infection experiments; H.K. helped with the infection experiments; H.H. helped to generate Tlr5−/− mice; C.C. helped with the infection experiments; T.K., K.J.I. and O.T. provided advice for the experiments; M.M. provided advice for the experiments and manuscript; K.T. helped to generate Tlr5−/− mice and to design experiments; and S.A. designed all the experiments and prepared the manuscript.

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Correspondence to Shizuo Akira.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Generation of Tlr5−/− mice. (PDF 1622 kb)

Supplementary Fig. 2

CD11c+ LPCs produce IL-6 in response to TLR2 and TLR9 stimulation. (PDF 791 kb)

Supplementary Fig. 3

Surface phenotype of MLN cells 2 d after oral S. typhimurium infection. (PDF 1128 kb)

Supplementary Fig. 4

Uptake of S. typhimurium in situ. (PDF 903 kb)

Supplementary Table 1

Primer sequences. (PDF 21 kb)

Supplementary Methods (PDF 80 kb)

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Uematsu, S., Jang, M., Chevrier, N. et al. Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nat Immunol 7, 868–874 (2006). https://doi.org/10.1038/ni1362

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