scholarly journals Proinflammatory cytokine-induced tight junction remodeling through dynamic self-assembly of claudins

2014 ◽  
Vol 25 (18) ◽  
pp. 2710-2719 ◽  
Author(s):  
Christopher T. Capaldo ◽  
Attila E. Farkas ◽  
Roland S. Hilgarth ◽  
Susanne M. Krug ◽  
Mattie F. Wolf ◽  
...  
Keyword(s):  
Self Assembly ◽  
Barrier Function ◽  
Molecular Mechanisms ◽  
Barrier Properties ◽  
Interferon Γ ◽  
Mucosal Inflammation ◽  
Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
Self Assembling ◽  
Factor Α

Tight junctions (TJs) are dynamic, multiprotein intercellular adhesive contacts that provide a vital barrier function in epithelial tissues. TJs are remodeled during physiological development and pathological mucosal inflammation, and differential expression of the claudin family of TJ proteins determines epithelial barrier properties. However, the molecular mechanisms involved in TJ remodeling are incompletely understood. Using acGFP-claudin 4 as a biosensor of TJ remodeling, we observed increased claudin 4 fluorescence recovery after photobleaching (FRAP) dynamics in response to inflammatory cytokines. Interferon γ and tumor necrosis factor α increased the proportion of mobile claudin 4 in the TJ. Up-regulation of claudin 4 protein rescued these mobility defects and cytokine-induced barrier compromise. Furthermore, claudins 2 and 4 have reciprocal effects on epithelial barrier function, exhibit differential FRAP dynamics, and compete for residency within the TJ. These findings establish a model of TJs as self-assembling systems that undergo remodeling in response to proinflammatory cytokines through a mechanism of heterotypic claudin-binding incompatibility.

scholarly journals PGC-1α mediates a metabolic host defense response in human airway epithelium during rhinovirus infections

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aubrey N. Michi ◽  
Bryan G. Yipp ◽  
Antoine Dufour ◽  
Fernando Lopes ◽  
David Proud
Keyword(s):  
Host Defense ◽  
Barrier Function ◽  
Bacterial Infections ◽  
Molecular Mechanisms ◽  
Cellular Damage ◽  
Epithelial Barrier ◽  
Airway Epithelial ◽  
Barrier Dysfunction ◽  
Epithelial Barrier Function ◽  
Epithelial Damage

AbstractHuman rhinoviruses (HRV) are common cold viruses associated with exacerbations of lower airways diseases. Although viral induced epithelial damage mediates inflammation, the molecular mechanisms responsible for airway epithelial damage and dysfunction remain undefined. Using experimental HRV infection studies in highly differentiated human bronchial epithelial cells grown at air-liquid interface (ALI), we examine the links between viral host defense, cellular metabolism, and epithelial barrier function. We observe that early HRV-C15 infection induces a transitory barrier-protective metabolic state characterized by glycolysis that ultimately becomes exhausted as the infection progresses and leads to cellular damage. Pharmacological promotion of glycolysis induces ROS-dependent upregulation of the mitochondrial metabolic regulator, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), thereby restoring epithelial barrier function, improving viral defense, and attenuating disease pathology. Therefore, PGC-1α regulates a metabolic pathway essential to host defense that can be therapeutically targeted to rescue airway epithelial barrier dysfunction and potentially prevent severe respiratory complications or secondary bacterial infections.

scholarly journals The impact of lactoferrin with different levels of metal saturation on the intestinal epithelial barrier function and mucosal inflammation

BioMetals ◽  
2016 ◽  
Vol 29 (6) ◽  
pp. 1019-1033 ◽  
Author(s):  
Grzegorz Majka ◽  
Grażyna Więcek ◽  
Małgorzata Śróttek ◽  
Klaudyna Śpiewak ◽  
Małgorzata Brindell ◽  
...  
Keyword(s):  
Barrier Function ◽  
Mucosal Inflammation ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
The Impact ◽  
Different Levels

scholarly journals Microbiota-derived butyrate dynamically regulates intestinal homeostasis through regulation of actin-associated protein synaptopodin

2020 ◽  
Vol 117 (21) ◽  
pp. 11648-11657 ◽  
Author(s):  
Ruth X. Wang ◽  
J. Scott Lee ◽  
Eric L. Campbell ◽  
Sean P. Colgan
Keyword(s):  
Wound Healing ◽  
Barrier Function ◽  
Critical Role ◽  
Actin Binding ◽  
Mucosal Inflammation ◽  
Epithelial Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Epithelial Barrier ◽  
Intestinal Homeostasis ◽  
Epithelial Barrier Function

The intestinal mucosa exists in dynamic balance with trillions of luminal microbes. Disruption of the intestinal epithelial barrier, commonly observed in mucosal inflammation and diseases such as inflammatory bowel diseases (IBDs), is often associated with dysbiosis, particularly decreases in species producing short-chain fatty acids (SCFAs), such as butyrate. It remains unclear to what extent microbiota-derived factors contribute to the overall maintenance of intestinal homeostasis. Initial studies revealed that butyrate selectively promotes epithelial barrier function and wound healing. We aimed to define the specific mechanism(s) through which butyrate contributes to these epithelial responses. Guided by an unbiased profiling approach, we identified the dominant regulation of the actin-binding protein synaptopodin (SYNPO). Extensions of this work revealed a role for SYNPO in intestinal epithelial barrier function and wound healing. SYNPO was localized to the intestinal epithelial tight junction and within F-actin stress fibers where it is critical for barrier integrity and cell motility. Butyrate, but not other SCFAs, induced SYNPO in epithelial cell lines and murine colonic enteroids through mechanisms possibly involving histone deacetylase inhibition. Moreover, depletion of the microbiota abrogated expression of SYNPO in the mouse colon, which was rescued with butyrate repletion. Studies inSynpo-deficient mice demonstrated exacerbated disease susceptibility and increased intestinal permeability in a dextran sulfate sodium colitis model. These findings establish a critical role for the microbiota and their products, specifically butyrate, in the regulated expression of SYNPO for intestinal homeostasis and reveal a direct mechanistic link between microbiota-derived butyrate and barrier restoration.

Ochratoxin A increases permeability through tight junctions by removal of specific claudin isoforms

2004 ◽  
Vol 287 (5) ◽  
pp. C1412-C1417 ◽  
Author(s):  
John McLaughlin ◽  
Philip J. Padfield ◽  
Julian P. H. Burt ◽  
Catherine A. O'Neill
Keyword(s):  
Ochratoxin A ◽  
Bacterial Translocation ◽  
Barrier Function ◽  
Electrical Resistance ◽  
Barrier Properties ◽  
Transepithelial Electrical Resistance ◽  
Intestinal Cell ◽  
Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
Intestinal Cell Line

On interaction with the intestine, the mycotoxin ochratoxin A is know to cause rapid inflammation, diarrhea, and increased bacterial translocation. All these effects are consistent with a decrease in epithelial barrier function. However, this has not been shown directly. We determined that ochratoxin A is able to reduce the barrier properties of the model intestinal cell line Caco-2. Over 24 h, ochratoxin A reduces the transepithelial electrical resistance of Caco-2 monolayers growing on Transwell filters by ∼40%. At the same time, the permeability of the monolayer is increased with respect to 4- and 10-kDa FITC dextrans, but not to 20- or 40-kDa dextrans. Immunoblotting and immuofluorescence reveal that the decrease in barrier properties is concomitant with disappearance of claudins 3 and 4, but not claudin 1 from Caco-2 cell membranes. These results suggest that ochratoxin A is able to modulate the barrier function of Caco-2 cells by removal of specific claudin isoforms.

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