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

Jongdae Lee, Ji Hun Mo, Kyoko Katakura, Irit Alkalay, Adam N. Rucker, Yu Tsueng Liu, Hyun Ku Lee, Carol Shen, Gady Cojocaru, Steve Shenouda, Martin Kagnoff, Lars Eckmann, Yinon Ben-Neriah, Eyal Raz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

513 Scopus citations


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 IκBα 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.

Original languageAmerican English
Pages (from-to)1327-1336
Number of pages10
JournalNature Cell Biology
Issue number12
StatePublished - Dec 2006

Bibliographical note

Funding Information:
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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