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Nature Cell Biology 8, 1327–1336 (1 December 2006) | doi:10.1038/ncb1500

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

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.