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Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells

Nature Cell Biology volume 8, pages 1327–1336 (2006)Cite this article

Abstract

The mechanisms by which commensal bacteria suppress inflammatory signalling in the gut are still unclear. Here, we present a cellular mechanism whereby the polarity of intestinal epithelial cells (IECs) has a major role in colonic homeostasis. TLR9 activation through apical and basolateral surface domains have distinct transcriptional responses, evident by NF-κB activation and cDNA microarray analysis. Whereas basolateral TLR9 signals IκBα degradation and activation of the NF-κB pathway, apical TLR9 stimulation invokes a unique response in which ubiquitinated IκB accumulates in the cytoplasm preventing NF-κB activation. Furthermore, apical TLR9 stimulation confers intracellular tolerance to subsequent TLR challenges. IECs in TLR9-deficient mice, when compared with wild-type and TLR2-deficient mice, display a lower NF-κB activation threshold and these mice are highly susceptible to experimental colitis. Our data provide a case for organ-specific innate immunity in which TLR expression in polarized IECs has uniquely evolved to maintain colonic homeostasis and regulate tolerance and inflammation.

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Figure 1: Domain-specific response to TLR ligands in polarized IECs.
Figure 2: Polarized IECs response to TLR9 ligand and surface expression of TLR9 in IECs.
Figure 3: Chloroquine treatment augments, rather than inhibits TLR9 signalling in IECs.
Figure 4: Unique TLR9 signalling in polarized IECs.
Figure 5: Distinct sets of genes are activated by apical TLR9.
Figure 6: Apical TLR9 stimulation aborts subsequent TLR signalling from the basolateral IEC domain.
Figure 7: TLR9 signalling provides protection against colonic injury.

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Acknowledgements

We thank P. Lee, J. Carmen, N. Varki, L. She, C. Yoon and M. Chung for technical assistance, S. Akira for TLR-null mice, and L. Beck and H. Cottam for critical reading of the manuscript. We also would like to thank B. Brinkman for his assistance in confocal imaging (UCSD Neuroscience Microscopy Shared Facility, NINDS grant P30 NS047101). This work is supported by National Institutes of Health (NIH) grants AI57709, DK35108 and AI40682 (E.R.), AI56075 and RR17030 (L.E.) European Commission (Program 6) Network of Excellence RUBICON and Israel Science Foundation-Centers of Excellence Program (Y.B.-N.).

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Authors and Affiliations

  1. Department of Medicine, University of California, San Diego, La Jolla, 92093–0663, CA, USA

    Jongdae Lee, Ji-Hun Mo, Kyoko Katakura, Adam N. Rucker, Yu-Tsueng Liu, Carol Shen, Steve Shenouda, Martin Kagnoff, Lars Eckmann & Eyal Raz

  2. The Lautenberg Center for Immunology, Hebrew-University-Hadassah Medical School, Jerusalem, 91120, Israel

    Irit Alkalay, Gady Cojocaru & Yinon Ben-Neriah

  3. Department of Immunology, The Scripps Research Institute, La Jolla, 92037, CA, USA

    Hyun-Ku Lee

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Lee, J., Mo, JH., Katakura, K. et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nat Cell Biol 8, 1327–1336 (2006). https://doi.org/10.1038/ncb1500

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