Loss of Desmoglein 2 Contributes to the Pathogenesis of Crohnʼs Disease

Spindler, Volker; Meir, Michael; Vigh, Balázs; Flemming, Sven; Hütz, Katharina; Germer, Christoph‐Thomas; Waschke, Jens; Schlegel, Nicolas

doi:10.1097/mib.0000000000000486

Cited by 41 publications

(85 citation statements)

References 42 publications

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“…However, in the course of several hours treatment with anisomycin impaired barrier function also. This is in line with our previous data, as treatment with TNFα activated p38MAPK which resulted in loss of cell cohesion and increased permeability as well as reduction of Dsg2 at the cell borders 19 .…”

Section: Discussionsupporting

confidence: 93%

“…Both, an antibody directed against Dsg2 as well as siRNA-mediated Dsg2 depletion resulted in loss of cell cohesion and reduced barrier function 12, 19, 22 . Since Dsg2 was missing at cell junctions in patients suffering from CD and a Dsg-specific tandem peptide ameliorated barrier dysfunction in response to TNF-α, which is regarded as a central cytokine in CD pathogenesis, we concluded that impaired Dsg2 may contribute to pathogenesis of inflammatory bowel diseases (IBD) 19 . This is supported by the finding that cytokines in IBD via matrix metalloproteinase 9 (MMP9) and a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) cause ectodomain cleavage of Dsg2, the products of which further compromised barrier integrity 18 .…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, increased intestinal permeability is associated with severe inflammatory disorders such as Crohn’s disease (CD) 14–17 . Especially, Dsg2 has already been shown to play a role in inflammation 18 and in the pathogenesis of CD as it was strongly reduced in the mucosa of patients suffering from CD whereas the AJ molecule E-cadherin was unaffected 19 . Tumor necrosis factor-α (TNF-α), which is a central cytokine in CD, resulted in impaired barrier properties whereas a tandem peptide stabilizing desmosomal adhesion rescued barrier function.…”

Section: Introductionmentioning

confidence: 99%

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Desmoglein 2 regulates the intestinal epithelial barrier via p38 mitogen-activated protein kinase

Ungewiß

Vielmuth

Suzuki

et al. 2017

Sci Rep

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Intestinal epithelial barrier properties are maintained by a junctional complex consisting of tight junctions (TJ), adherens junctions (AJ) and desmosomes. Desmoglein 2 (Dsg2), an adhesion molecule of desmosomes and the only Dsg isoform expressed in enterocytes, is required for epithelial barrier properties and may contribute to barrier defects in Crohn’s disease. Here, we identified extradesmosomal Dsg2 on the surface of polarized enterocytes by Triton extraction, confocal microscopy, SIM and STED. Atomic force microscopy (AFM) revealed Dsg2-specific binding events along the cell border on the surface of enterocytes with a mean unbinding force of around 30pN. Binding events were blocked by an inhibitory antibody targeting Dsg2 which under same conditions activated p38MAPK but did not reduce cell cohesion. In enterocytes deficient for Dsg2, p38MAPK activity was reduced and both barrier integrity and reformation were impaired. Dsc2 rescue did not restore p38MAPK activity indicating that Dsg2 is required. Accordingly, direct activation of p38MAPK in Dsg2-deficient cells enhanced barrier reformation demonstrating that Dsg2-mediated activation of p38MAPK is crucial for barrier function. Collectively, our data show that Dsg2, beside its adhesion function, regulates intestinal barrier function via p38MAPK signalling. This is in contrast to keratinocytes and points towards tissue-specific signalling functions of desmosomal cadherins.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Desmoglein 2 regulates the intestinal epithelial barrier via p38 mitogen-activated protein kinase

Ungewiß

Vielmuth

Suzuki

et al. 2017

Sci Rep

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“…This was shown to be mediated by the p38 MAPK pathway due to a significant dephosphorylation of p38 MAPK after the application of GDNF in vitro (36). The latter mechanism has been previously shown to stabilize the intestinal epithelial barrier (51). Additionally, GDNF induced a cAMP/PKA-dependent increase of proliferation and augmented epithelial wound healing.…”

Section: Gdnf Directly Promotes Barrier Maturation and Proliferation mentioning

confidence: 87%

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

Meir

Flemming

Burkard

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Regulation of the intestinal epithelial barrier is a differentiated process, which is profoundly deranged in inflammatory bowel diseases. Recent data provide evidence that the glial cell line-derived neurotrophic factor (GDNF) is critically involved in intestinal epithelial wound healing and barrier maturation and exerts antiapoptotic effects under certain conditions. Furthermore, not only the enteric nervous system, but also enterocytes synthesize GDNF in significant amounts, which points to a potential para- or autocrine signaling loop between enterocytes. Apart from direct effects of GDNF on enterocytes, an immunomodulatory role of this protein has been previously assumed because of a significant reduction of inflammation in a model of chronic inflammatory bowel disease after application of GDNF. In this review we summarize the current knowledge of GDNF on intestinal epithelial barrier regulation and discuss the novel role for GDNF as a regulator of intestinal barrier functions in health and disease.

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“…Decreased expression of AJ and TJ proteins is not the only mechanism that underlies functional defects of epithelial junctions in the inflamed intestinal mucosa, where junctional proteins are frequently redistributed from the cell-cell contact into cytoplasmic compartments [25, 94, 95]. Vesicle trafficking plays a key role in the establishment and remodeling of epithelial junctions at the plasma membrane.…”

Section: Altered Trafficking Of Aj/tj Proteins In the Inflamed Gutmentioning

confidence: 99%

Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms

Lechuga

Ivanov

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

202

164

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The intestinal epithelium forms a key protective barrier that separates internal organs from the harmful environment of the gut lumen. Increased permeability of the gut barrier is a common manifestation of different inflammatory disorders contributing to the severity of disease. Barrier permeability is controlled by epithelial adherens junctions and tight junctions. Junctional assembly and integrity depend on fundamental homeostatic processes such as cell differentiation, rearrangements of the cytoskeleton, and vesicle trafficking. Alterations of intestinal epithelial homeostasis during mucosal inflammation may impair structure and remodeling of apical junctions, resulting in increased permeability of the gut barrier. In this review, we summarize recent advances in our understanding of how altered epithelial homeostasis affects the structure and function of adherens junctions and tight junctions in the inflamed gut. Specifically, we focus on the transcription reprogramming of the cell, alterations in the actin cytoskeleton, and junctional endocytosis and exocytosis. We pay special attention to knockout mouse model studies and discuss the relevance of these mechanisms to human gastrointestinal disorders.

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Loss of Desmoglein 2 Contributes to the Pathogenesis of Crohnʼs Disease

Abstract: We show an important role of p38MAPK-mediated regulation of desmosomal adhesion resulting in upregulation of claudin-2 in CD. Our data suggest peptide-mediated strengthening of impaired Dsg2 adhesion as a novel therapeutic approach in CD.

Cited by 41 publications

References 42 publications

Desmoglein 2 regulates the intestinal epithelial barrier via p38 mitogen-activated protein kinase

Desmoglein 2 regulates the intestinal epithelial barrier via p38 mitogen-activated protein kinase

The glial cell-line derived neurotrophic factor: a novel regulator of intestinal barrier function in health and disease

Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms

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