Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions

Schlingmann, Barbara; Overgaard, Christian E.; Molina, Samuel A.; Lynn, K. Sabrina; Mitchell, Leslie A.; White, StevenClaude Dorsainvil; Mattheyses, Alexa L.; Guidot, David M.; Capaldo, Christopher; Koval, Michael

doi:10.1038/ncomms12276

Cited by 86 publications

(67 citation statements)

References 63 publications

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“…To measure tight junction function, TER measurements of NhBE cells that were cultured on transwell‐permeable supports was performed. Cells were placed in Ringer's saline buffer (150 mM NaCl, 2 mM CaCl 2 , 1 mM MgCl 2 , 10 mM glucose, and 10 mM HEPES, pH 7.4) (43), and TER was read by using an Ohmmeter (World Precision Instruments, Sarasota, FL, USA) with chopstick electrodes. In brief, NhBE cells were pretreated with 30 μM PIO overnight, followed by washing with PBS (that contained Ca 2+ and Mg 2+ ) twice, and subsequently treated with PAO1 with an MOI of 10 and 50 μM C12‐HSL.…”

Section: Methodsmentioning

confidence: 99%

Peroxisome proliferator‐activated receptor‐γ agonists attenuate biofilm formation by Pseudomonas aeruginosa

et al. 2017

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Pseudomonas aeruginosa is a significant contributor to recalcitrant multidrug-resistant infections, especially in immunocompromised and hospitalized patients. The pathogenic profile of P. aeruginosa is related to its ability to secrete a variety of virulence factors and to promote biofilm formation. Quorum sensing (QS) is a mechanism wherein P. aeruginosa secretes small diffusible molecules, specifically acyl homo serine lactones, such as N-(3-oxo-dodecanoyl)-l-homoserine lactone (3O-C12-HSL), that promote biofilm formation and virulence via interbacterial communication. Strategies that strengthen the host's ability to inhibit bacterial virulence would enhance host defenses and improve the treatment of resistant infections. We have recently shown that peroxisome proliferator-activated receptor g (PPARg) agonists are potent immunostimulators that play a pivotal role in host response to virulent P. aeruginosa. Here, we show that QS genes in P. aeruginosa (strain PAO1) and 3O-C12-HSL attenuate PPARg expression in bronchial epithelial cells. PAO1 and 3O-C12-HSL induce barrier derangements in bronchial epithelial cells by lowering the expression of junctional proteins, such as zonula occludens-1, occludin, and claudin-4. Expression of these proteins was restored in cells that were treated with pioglitazone, a PPARg agonist, before infection with PAO1 and 3O-C12-HSL. Barrier function and bacterial permeation studies that have been performed in primary human epithelial cells showed that PPARg agonists are able to restore barrier integrity and function that are disrupted by PAO1 and 3O-C12-HSL. Mechanistically, we show that these effects are dependent on the induction of paraoxonase-2, a QS hydrolyzing enzyme, that mitigates the effects of QS molecules. Importantly, our data show that pioglitazone, a PPARg agonist, significantly inhibits biofilm formation on epithelial cells by a mechanism that is mediated via paraoxonase-2. These findings elucidate a novel role for PPARg in host defense against P. aeruginosa. Strategies that activate PPARg can provide a therapeutic complement for treatment of resistant P. aeruginosa infections.-

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Section: Methodsmentioning

confidence: 99%

Peroxisome proliferator‐activated receptor‐γ agonists attenuate biofilm formation by Pseudomonas aeruginosa

et al. 2017

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“…The fluorescence Z-series images were visualized using Olympus FV 1000/TIRF laser scanning confocal microscope. Images were Z-stacked using FUJI software (NIH Image J) [22]. …”

Section: Methodsmentioning

confidence: 99%

Calibrated flux measurements reveal a nanostructure-stimulated transcytotic pathway

Stewart

Koval

Molina

et al. 2017

Experimental Cell Research

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Transport of therapeutic agents across epithelial barriers is an important element in drug delivery. Transepithelial flux is widely used as a measure of transit across an epithelium, however it is most typically employed as a relative as opposed to absolute measure of molecular movement. Here, we have used the calcium switch approach to measure the maximum rate of paracellular flux through unencumbered intercellular junctions as a method to calibrate the flux rates for a series of tracers ranging in 0.6 to 900 kDa in size across barriers composed of human colon epithelial (Caco-2) cells. We then examined the effects of nanostructured films (NSFs) on transepithelial transport. Two different NSF patterns were used, Defined Nanostructure (DN) 2 imprinted on polypropylene (PP) and DN3 imprinted on polyether ether ketone (PEEK). NSFs made direct contact with cells and decreased their barrier function, as measured by transepithelial resistance (TER), however cell viability was not affected. When NSF-induced transepithelial transport of Fab fragment (55 kDa) and IgG (160 kDa) was measured, it was unexpectedly found to be significantly greater than the maximum paracellular rate as predicted using cells cultured in low calcium. These data suggested that NSFs stimulate an active transport pathway, most likely transcytosis, in addition to increasing paracellular flux. Transport of IgG via transcytosis was confirmed by immunofluorescence confocal microscopy, since NSFs induced a significant level of IgG endocytosis by Caco-2 cells. Thus, NSF-induced IgG flux was attributable to both transcytosis and the paracellular route. These data provide the first demonstration that transcytosis can be stimulated by NSFs and that this was concurrent with increased paracellular permeability. Moreover, NSFs with distinct architecture paired with specific substrates have the potential to provide an effective means to regulate transepithelial transport in order to optimize drug delivery.

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“…Organ-specific features of tight junction-dependent barrier function have been studied in the lungs (Schlingmann et al 2016), kidneys (Pei et al 2016), and gastrointestinal tract (Wada et al 2013), but have been analyzed in greatest detail in the context of gastrointestinal disease (Clayburgh et al 2005; Heller et al 2005; Weber et al 2008, 2010; Su et al 2009; Marchiando et al 2010a). In vitro, reductionist models of barrier loss in inflammatory bowel disease (IBD) include epithelial responses to exogenous tumor necrosis factor-α (TNF) and interleukin-13 (IL-13), which have each been implicated in Crohn’s disease and ulcerative colitis, the two forms of IBD.…”

Section: Tumor Necrosis Factor-mediated Regulation Of Tight Junction mentioning

confidence: 99%

Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease

Buckley

Turner

2017

Cold Spring Harb Perspect Biol

535

370

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Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing intrusion by luminal materials. Intestinal epithelia therefore play a central role in regulating interactions between the mucosal immune system and luminal contents, which include dietary antigens, a diverse intestinal microbiome, and pathogens. The paracellular space is sealed by the tight junction, which is maintained by a complex network of protein interactions. Tight junction dysfunction has been linked to a variety of local and systemic diseases. Two molecularly and biophysically distinct pathways across the intestinal tight junction are selectively and differentially regulated by inflammatory stimuli. This review discusses the mechanisms underlying these events, their impact on disease, and the potential of using these as paradigms for development of tight junction-targeted therapeutic interventions.

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Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions

Cited by 86 publications

References 63 publications

Peroxisome proliferator‐activated receptor‐γ agonists attenuate biofilm formation by Pseudomonas aeruginosa

Peroxisome proliferator‐activated receptor‐γ agonists attenuate biofilm formation by Pseudomonas aeruginosa

Calibrated flux measurements reveal a nanostructure-stimulated transcytotic pathway

Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease

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