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Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis
Department of Pharmacy, Uppsala University, Uppsala.
Division of Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping.ORCID iD: 0000-0002-8391-1576
Department of Pharmacy, Uppsala University, Uppsala; Division of Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping.
Division of Surgery, Department of Clinical and Experimental Medicine, Linköping University, Linköping.
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2008 (English)In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 88, no 11, p. 1215-26Article in journal (Refereed) Published
Abstract [en]

Crohn's disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epithelium-derived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv+) or lacking (inv-) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of beta1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv+ Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, P<0.01) and ileal mucosa (268+/-47% of control; P<0.01), whereas inv bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size- and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of beta1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv+ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of beta1-integrin and stimulated uptake of nanoparticles via invasin-dependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.

Place, publisher, year, edition, pages
New York, USA: Nature Publishing Group, 2008. Vol. 88, no 11, p. 1215-26
Keywords [en]
Barrier function, β1-integrin, Caco-2 cells, confocal microscopy, Crohn's disease, Ussing chambers
National Category
Medical and Health Sciences Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-40021DOI: 10.1038/labinvest.2008.86ISI: 000260427600008PubMedID: 18810251Scopus ID: 2-s2.0-54949156390OAI: oai:DiVA.org:oru-40021DiVA, id: diva2:774703
Available from: 2014-12-28 Created: 2014-12-28 Last updated: 2018-01-11Bibliographically approved

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