Caveolin-1–dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo

Marchiando, Amanda M.; Shen, Le; Graham, W. Vallen; Weber, Christopher; Schwarz, Brad T.; Austin, Jotham R.; Raleigh, David R.; Guan, Yanfang; Watson, Alastair; Montrose, Marshall H.; Turner, Jerrold R.

doi:10.1084/jem2074oia10

Cited by 82 publications

(153 citation statements)

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“…Increased gut permeability has been observed in multiorgan failure and in gastrointestinal disease 39,40 For example, in Crohn's disease, inflammation and loss of gut barrier integrity are associated with TNF as they are dramatically decreased by anti-TNF treatment. 41 As TNF injection has been reported to lead to loss of gut permeability, 42 it is interesting that MMP7 À / À mice were also substantially protected against the TNFinduced lethal response (Figure 3i). …”

Section: Mmp7 Is Expressed and Activated In The Paneth Cells Of The Imentioning

confidence: 93%

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

et al. 2014

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Matrix metalloproteinase 7 (MMP7) is a member of the MMP family. In the small intestine, MMP7 is responsible for activating α-defensins, which are broad-spectrum anti-microbial peptides produced by the Paneth cells. We report that MMP7(-/-) mice are resistant to LPS-induced lethality and that this resistance is correlated with reduced levels of systemic cytokines. LPS induced the upregulation and activation of MMP7 in the small intestine, degranulation of the Paneth cells, and induction of intestinal permeability in MMP7(+/+) mice. In MMP7(-/-) mice, both LPS-induced intestinal permeability and consequent bacterial translocation to the mesenteric lymph nodes were reduced. Based on gene expression analysis and evaluation of intestinal damage, we attribute the protected state of MMP7(-/-) mice to reduced intestinal inflammation. Interestingly, we found that different α-defensins, namely Crp1 (DEFA1) and Crp4 (DEFA4), can stimulate IL-6 release in macrophages and ileum explants in a TLR4 independent way. We conclude that absence of MMP7 protects mice from LPS-induced intestinal permeability and lethality, and suggest that MMP7-activated α-defensins, in addition to their previously recognized bactericidal and anti-inflammatory roles, may exhibit pro-inflammatory activities in the intestine by activating macrophages and amplifying the local inflammatory response in the gut, leading to intestinal leakage and subsequent increase in systemic inflammation.

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Section: Mmp7 Is Expressed and Activated In The Paneth Cells Of The Imentioning

confidence: 93%

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

et al. 2014

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“…Intracellular vesicular membrane transport has been considered as a key process in the formation of tight junction domains (22). Other investigators have shown that caveolae are involved in the trafficking of occludin (13,30), and caveolin-1 directly regulates small GTPase Rab5 that is localized at the tight junction (8). Furthermore, intracellular movement of ClC-2 has been shown to involve Rab5 (6).…”

Section: Clc-2 Is Closely Associated With the Tight Junction During Ementioning

confidence: 99%

“…Cytotoxic necrotizing factor-1, a toxin from Escherichia coli, activates the small GTPase RhoA and causes caveolae-mediated endocytosis of occludin (9). Recently, the occludin caveolin-1 complex has been shown to be involved in cytokine-mediated changes in the epithelial barrier (13,30,39). Interestingly, in view of the involvement of occludin in ClC-2-mediated barrier function, we were able to demonstrate association of ClC-2 with caveolin-1 and Rab5 by a proteomic approach, coimmunoprecipitation, and confocal immunofluorescence.…”

Section: C183mentioning

confidence: 99%

“…The functional roles of the tight junction proteins are being increasingly understood. For instance, although occludin has for a long time been considered a structural protein, recently it has been shown to have critical roles in cytokine-induced barrier dysfunction (13,39). Besides controlling paracellular permeability, tight junctions are also considered to be a signaling platform for cellular processes including morphogenesis, cell polarity and differentiation via interactions with actin cytoskeletal elements, kinases and phosphatases, and the intracellular trafficking apparatus (33,35).…”

mentioning

confidence: 99%

“…Various modes of intracellular transport such as clathrin-mediated transport, caveolar transport, and micropinocytosis, as well as signaling molecules such as small GTPase Rabs and their adaptors have been shown to regulate biogenesis and function of tight junctions (13,14,45).We hypothesized that ClC-2 plays an important role in the development and maintenance of the tight junction barrier. Our results show that ClC-2 plays an important role in the modulation of tight junctions by influencing caveolar trafficking of the tight junction protein occludin.…”

mentioning

confidence: 99%

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Chloride channel ClC-2 modulates tight junction barrier function via intracellular trafficking of occludin

Nighot

Blikslager

2012

American Journal of Physiology-Cell Physiology

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Previously, we have demonstrated that the chloride channel ClC-2 modulates intestinal mucosal barrier function. In the present study, we investigated the role of ClC-2 in epithelial barrier development and maintenance in Caco-2 cells. During early monolayer formation, silencing of ClC-2 with small interfering (si)RNA led to a significant delay in the development of transepithelial resistance (TER) and disruption of occludin localization. Proteomic analysis employing liquid chromatography-mass spectrometry /mass spectrometry revealed association of ClC-2 with key proteins involved in intracellular trafficking, including caveolin-1 and Rab5. In ClC-2 siRNA-treated cells, occludin colocalization with caveolin-1 was diffuse and in the subapical region. Subapically distributed occludin in ClC-2 siRNA-treated cells showed marked colocalization with Rab5. To study the link between ClC-2 and trafficking of occludin in confluent epithelial monolayers, a Caco-2 cell clone expressing ClC-2 short hairpin (sh)RNA was established. Disruption of caveolae with methyl-β-cyclodextrin (MβCD) caused a marked drop in TER and profound redistribution of caveolin-1-occludin coimmunofluorescence in ClC-2 shRNA cells. In ClC-2 shRNA cells, focal aggregations of Rab5-occludin coimmunofluorescence were present within the cytoplasm. Wortmannin caused an acute fall in TER in ClC-2 shRNA cells and subapical, diffuse redistribution of Rab5-occludin coimmunofluorescence in ClC-2 shRNA cells. An endocytosis and recycling assay for occludin revealed higher basal rate of endocytosis of occludin in ClC-2 shRNA cells. Wortmannin significantly reduced the rate of recycling of occludin in ClC-2 shRNA cells. These data clearly indicate that ClC-2 plays an important role in the modulation of tight junctions by influencing caveolar trafficking of the tight junction protein occludin.

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Electrophysiologic Analysis of Tight Junction Size and Charge Selectivity

et al. 2021

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Tight junctions form selectively permeable barriers that limit paracellular flux across epithelial‐lined surfaces. Rather than being absolute barriers, tight junctions in many tissues allow ions, water, and other small molecules to cross on the basis of size and charge selectivity via the high‐capacity pore pathway. Most probes currently used to assess tight junction permeability exceed the maximum size capacity of the pore pathway. As a result, available analytical tools have generally been limited to measurement of transepithelial electrical resistances. These provide no information regarding size selectivity and, therefore, cannot be used to distinguish between the pore pathway and the leak pathway, a low‐capacity route that accommodates larger macromolecules. This article describes use of dilution potential and bi‐ionic potential measurements for analysis of tight junction size and charge selectivity within monolayers of cultured epithelial cells. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Culture of MDCK monolayers on semipermeable supports and induction of claudin‐2 expression Basic Protocol 2: Configuring voltage/current clamp and other equipment Basic Protocol 3: Measuring dilution and bi‐ionic potentials Basic Protocol 4: Calculating ion permeabilities and pore diameter Support Protocol: Preparation of agar bridges and electrophysiology rig setup

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Caveolin-1–dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo

Cited by 82 publications

References 1 publication

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

Chloride channel ClC-2 modulates tight junction barrier function via intracellular trafficking of occludin

Electrophysiologic Analysis of Tight Junction Size and Charge Selectivity

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