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

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433 Citations (Scopus)

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 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 languageEnglish
Pages (from-to)1327-1336
Number of pages10
JournalNature Cell Biology
Volume8
Issue number12
DOIs
Publication statusPublished - 1 Dec 2006

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    Lee, J., Mo, J. H., Katakura, K., Alkalay, I., Rucker, A. N., Liu, Y. T., Lee, H. K., Shen, C., Cojocaru, G., Shenouda, S., Kagnoff, M., Eckmann, L., Ben-Neriah, Y., & Raz, E. (2006). Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. Nature Cell Biology, 8(12), 1327-1336. https://doi.org/10.1038/ncb1500