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Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis
Uppsala University.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Surgery .
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2008 (English)In: Laboratory Investigation, ISSN 0023-6837, E-ISSN 1530-0307, Vol. 88, no 11, 1215-1226 p.Article in journal (Refereed) Published
Abstract [en]

Crohns 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 beta 1-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 beta 1-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 beta 1-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
2008. Vol. 88, no 11, 1215-1226 p.
Keyword [en]
barrier function, beta 1-integrin, Caco-2 cells, confocal microscopy, Crohns disease, Ussing chambers
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-16079DOI: 10.1038/labinvest.2008.86OAI: oai:DiVA.org:liu-16079DiVA: diva2:133094
Available from: 2009-01-07 Created: 2009-01-07 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Mechanisms of bacterial-epithelial interaction in Crohn’s disease
Open this publication in new window or tab >>Mechanisms of bacterial-epithelial interaction in Crohn’s disease
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Crohn’s disease (CD) is believed to be initiated when an individual, who has agenetic predisposition either leading to a disturbance in the barrier functionand/or the innate immune system is exposed to triggering environmentalfactors, the most important being intraluminal bacteria. Genetic and functionalstudies have confirmed the Pattern-recognition receptors (PRRs), Nod2, TLR4and NALP3, as important mediators of the inflammatory process associatedwith disease progression. However, the mechanisms that link enteric bacteriaand barrier function in a background of genetic predisposition to CD are justbeginning to emerge. The general aim of this thesis was therefore to morethoroughly investigate the mechanisms of bacterial-epithelial interaction in CD.

Here we present evidence suggesting that the small bowel is able to inducetranscytosis of antigens after short term exposure to Yersinia pseudotuberculosis. This suggests that small bowel enterocytes are able toattain follicle associated epithelial (FAE) abilities and contribute to the barrierdysfunction observed in CD. Furthermore we report a positive effect of anti-TNFα treatment (infliximab) on the translocation of adherent invasive E.coli (AIEC) across the colonic mucosa of patients suffering from severe CD.

We also confirm the importance of the Nod-like receptors (NLRs) in thepathogenesis of CD by showing that combined polymorphisms in the genesencoding NALP3 and CARD8 confer susceptibility to CD among Swedish menand in addition to previous published results add a gender aspect on thegenotype-phenotype relationship in CD. Finally, we show that Nod2 is rapidlysubjected to ubiquitination followed by proteasomal degradation, henceproviding important clues about how NLR regulation might occur in the cell,suggesting that the ubiquitin-proteasome pathway is an important factor toconsider in the development of the disease.

In conclusion we report novel insights into the bacterial-epithelial interactionsoccurring in CD and contribute important clues about the origin of this disease.ISBN: 978-

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 71 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1113
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-21104 (URN)978-91-7393-667-5 (ISBN)
Public defence
2009-04-17, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:00 (English)
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Available from: 2009-09-29 Created: 2009-09-29 Last updated: 2009-09-29Bibliographically approved

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Schoultz, IdaGullberg, ElisabetCarlsson, AndersTafazoli, FaridehLerm, MariaMagnusson, Karl-EricSöderholm, Johan D

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Schoultz, IdaGullberg, ElisabetCarlsson, AndersTafazoli, FaridehLerm, MariaMagnusson, Karl-EricSöderholm, Johan D
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Faculty of Health SciencesSurgery Department of health and environmentMedical Microbiology Department of Surgery in Östergötland
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