Chloride channel ClC- 2 enhances intestinal epithelial tight junction barrier function via regulation of caveolin-1 and caveolar trafficking of occludin

Nighot, Prashant K.; Leung, Lana; Thomas, Y.

doi:10.1016/j.yexcr.2017.01.024

Cited by 34 publications

(21 citation statements)

References 59 publications

(76 reference statements)

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“…In addition, the ratio of the protein content of the tight junctional transmembrane protein occludin on the cell surface to the total occludin protein content was determined after cell surface biotinylation and streptavidin pull down. No significant differences were observed, although the ratio of surface occludin to total occludin may tentatively reflect the corresponding barrier properties as indicated by TEER and reported data for the internalization and trafficking of occludin in case of barrier impairment [22,23].…”

Section: Assessment Of Tight Junctional Proteins and Phosphorylated Csupporting

confidence: 59%

Site‐specific and endothelial‐mediated dysfunction of the alveolar‐capillary barrier in response to lipopolysaccharides

Janga

Cassidy

Wang

et al. 2017

J Cellular Molecular Medi

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Infectious agents such as lipopolysaccharides (LPS) challenge the functional properties of the alveolar‐capillary barrier (ACB) in the lung. In this study, we analyse the site‐specific effects of LPS on the ACB and reveal the effects on the individual cell types and the ACB as a functional unit. Monocultures of H441 epithelial cells and co‐cultures of H441 with endothelial cells cultured on Transwells® were treated with LPS from the apical or basolateral compartment. Barrier properties were analysed by the transepithelial electrical resistance (TEER), by transport assays, and immunostaining and assessment of tight junctional molecules at protein level. Furthermore, pro‐inflammatory cytokines and immune‐modulatory molecules were evaluated by ELISA and semiquantitative real‐time PCR. Liquid chromatography–mass spectrometry‐based proteomics (LS‐MS) was used to identify proteins and effector molecules secreted by endothelial cells in response to LPS. In co‐cultures treated with LPS from the basolateral compartment, we noticed a significant reduction of TEER, increased permeability and induction of pro‐inflammatory cytokines. Conversely, apical treatment did not affect the barrier. No changes were noticed in H441 monoculture upon LPS treatment. However, LPS resulted in an increased expression of pro‐inflammatory cytokines such as IL‐6 in OEC and in turn induced the reduction of TEER and an increase in SP‐A expression in H441 monoculture, and H441/OEC co‐cultures after LPS treatment from basolateral compartment. LS‐MS‐based proteomics revealed factors associated with LPS‐mediated lung injury such as ICAM‐1, VCAM‐1, Angiopoietin 2, complement factors and cathepsin S, emphasizing the role of epithelial–endothelial crosstalk in the ACB in ALI/ARDS.

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Section: Assessment Of Tight Junctional Proteins and Phosphorylated Csupporting

confidence: 59%

Site‐specific and endothelial‐mediated dysfunction of the alveolar‐capillary barrier in response to lipopolysaccharides

Janga

Cassidy

Wang

et al. 2017

J Cellular Molecular Medi

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“…These data suggest that after DSS-induced colitis, occludin and caveolin-1 are strongly associated in the cytosol of mice lacking ClC-2 but not in mice normally expressing ClC-2. In tandem, overexpression of ClC-2 in Caco-2 ClCN2 cells was reported to not only exhibit enhanced tight junction barrier function through significant increases in TER and reductions in apical-to-basal inulin flux, but this ClC-2 overexpression further connected ClC-2 to caveolin-1 and caveolar trafficking of occludin [77]. Specifically, ClC-2 overexpression in Caco-2 ClCN2 cells exhibited both significantly increased occludin protein and reduced endocytosis of occludin when compared to control cells while simultaneously diminishing both caveolin-1 protein and caveolae assembly [77].…”

Section: Clc-2 and Intestinal Repairmentioning

confidence: 94%

“…ClC-2 null mice treated with DSS also demonstrated significantly increased expression of claudin-2 and reduced occludin expression in the same study. Interestingly, a recent in vitro study established Caco-2 cells overexpressing ClC-2 (Caco-2 ClCN2 ), and this ClC-2 overexpression resulted in a decrease of the pore-forming claudin-2 protein while maintaining claudin-1 and claudin-4 protein levels to that of control cells [77]. As an aside, although cell volume and pH i is partially regulated by ClC-2 and thus the genetic knockout of ClC-2 can affect these intracellular factors, studies will be needed to determine if ClC-2-mediated changes in these intracellular factors have an effect on the tight junction [78,79].…”

Section: Clc-2 and Intestinal Repairmentioning

confidence: 99%

The Integral Role of Tight Junction Proteins in the Repair of Injured Intestinal Epithelium

Slifer

Blikslager

2020

IJMS

142

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The intestinal epithelial monolayer forms a transcellular and paracellular barrier that separates luminal contents from the interstitium. The paracellular barrier consists of a highly organized complex of intercellular junctions that is primarily regulated by apical tight junction proteins and tight junction-associated proteins. This homeostatic barrier can be lost through a multitude of injurious events that cause the disruption of the tight junction complex. Acute repair after injury leading to the reestablishment of the tight junction barrier is crucial for the return of both barrier function as well as other cellular functions, including water regulation and nutrient absorption. This review provides an overview of the tight junction complex components and how they link to other plasmalemmal proteins, such as ion channels and transporters, to induce tight junction closure during repair of acute injury. Understanding the components of interepithelial tight junctions and the mechanisms of tight junction regulation after injury is crucial for developing future therapeutic targets for patients experiencing dysregulated intestinal permeability.

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“…Caveolin-1 is an important structural and regulatory component of caveolae, which are involved in multiple physiological processes, such as proliferation, apoptosis, cell differentiation, and regulation of membrane trafficking processes including endocytosis, exocytosis and transcytosis (77,78). Caveolin-1 has also been reported to regulate the assembly of TJ proteins (79,80). In the lung, caveolin-1 is highly expressed in epithelial cells, fibroblasts, vascular endothelial cells, smooth muscle cells, macrophages and neutrophils, and it has been involved in several pathological features of ARDS, such as epithelial and endothelial cell death, inflammation, fibrosis and alterations of the alveolarcapillary permeability in the lung (77,81).…”

Section: Caveolin-1 As Regulator Of Lung Injurymentioning

confidence: 99%

New insights into the mechanisms of pulmonary edema in acute lung injury

2018

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Appearance of alveolar protein-rich edema is an early event in the development of acute respiratory distress syndrome (ARDS). Alveolar edema in ARDS results from a significant increase in the permeability of the alveolar epithelial barrier, and represents one of the main factors that contribute to the hypoxemia in these patients. Damage of the alveolar epithelium is considered a major mechanism responsible for the increased pulmonary permeability, which results in edema fluid containing high concentrations of extravasated macromolecules in the alveoli. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of pro-coagulant processes, cell death and mechanical stretch. The disruption of tight junction (TJ) complexes at the lateral contact of epithelial cells, the loss of contact between epithelial cells and extracellular matrix (ECM), and relevant changes in the communication between epithelial and immune cells, are deleterious alterations that mediate the disruption of the alveolar epithelial barrier and thereby the formation of lung edema in ARDS.

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Chloride channel ClC- 2 enhances intestinal epithelial tight junction barrier function via regulation of caveolin-1 and caveolar trafficking of occludin

Cited by 34 publications

References 59 publications

Site‐specific and endothelial‐mediated dysfunction of the alveolar‐capillary barrier in response to lipopolysaccharides

Site‐specific and endothelial‐mediated dysfunction of the alveolar‐capillary barrier in response to lipopolysaccharides

The Integral Role of Tight Junction Proteins in the Repair of Injured Intestinal Epithelium

New insights into the mechanisms of pulmonary edema in acute lung injury

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