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TLR4 Facilitates Translocation of Bacteria across Renal Collecting Duct Cells

Cécilia Chassin^*, Sophie Vimont, Françoise Cluzeaud^*, Marcelle Bens^*, Jean-Michel Goujon, Béatrice Fernandez, Alexandre Hertig, Eric Rondeau, Guillaume Arlet, Mathias W. Hornef^|| and Alain Vandewalle^*

^* INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon, BP 416, Paris, France; Université Paris 7, Denis Diderot, site Bichat, Service de Bactériologie, Hôpital Tenon, and Université Paris 6, Pierre et Marie Curie, site St. Antoine, and INSERM, U702, Hôpital Tenon, and Université Paris 6, Pierre et Marie Curie, site St. Antoine, Paris, and Unité de Pathologie Ultrastructurale et Expérimentale, Centre Hospitalier Universitaire de Poitiers, and Université de Poitiers, Poitiers, France; and ^|| Institute of Medical Microbiology and Hygiene, Hannover Medical School, Hannover, Germany

Correspondence: Dr. Alain Vandewalle, INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, UFR de Médecine Xavier Bichat, BP 416, 16 rue Henri Huchard, F-75870 Paris Cedex 18, France. Phone: 33-1-57-27-75-50; Fax: 33-1-57-27-75-31; E-mail: alain.vandewalle{at}inserm.fr

Received for publication December 3, 2007. Accepted for publication June 18, 2008.

Uropathogenic Escherichia coli (UPEC) are the most frequent causes of urinary tract infections and pyelonephritis. Renal medullary collecting duct (MCD) cells are the intrarenal site to which UPEC strains prefer to adhere and initiate an inflammatory response, but the ability of UPEC strains to translocate across impermeant MCD cells has not been demonstrated definitively. Here, several UPEC strains adhered to the apical surface and translocated across confluent murine inner MCD cells grown on filters. UPEC strains expressing cytolytic and vacuolating cytotoxins disrupted the integrity of cell layers, whereas noncytolytic UPEC strains passed through the cell layers without altering tight junctions. Apical-to-basal transcellular translocation was dramatically reduced after extinction of Toll-like receptor 4 (TLR4) and the lipid raft marker caveolin-1 by small interfering RNA. Furthermore, disruption of lipid raft integrity by filipin III and methyl-β-cyclodextrin significantly reduced both the transcellular translocation of UPEC across murine inner MCD cell layers and the stimulation of proinflammatory mediators. Bacterial translocation was also significantly reduced in primary cultures of TLR4-deficient mouse MCD cells compared with MCD cells from wild-type mice. Benzyl alcohol, an anesthetic that enhances membrane fluidity, favored the recruitment of caveolin-1 in lipid rafts and increased the translocation of UPEC across cultured TLR4-deficient MCD cells. These findings demonstrate that the transcellular translocation of UPEC strains across impermeant layers of MCD cells may occur through lipid rafts via a TLR4-facilitated process.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673