Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier

Kamekura, Ryuta; Nava, Porfirio; Feng, Mingli; Quirós, Miguel; Nishio, Hisahide; Weber, Dominique A.; Parkos, Charles A.; Nusrat, Asma

doi:10.1091/mbc.e15-03-0147

Cited by 46 publications

(71 citation statements)

References 75 publications

(98 reference statements)

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“…In this context, it was not surprising that GDNPs 2 affected the expression of numerous mitochondrial proteins, including malate dehydrogenase, creatine kinase B-type, ATP synthase subunit beta, and succinate dehydrogenase. In acute colitis, intestinal barrier function is compromised by dysregulation of the cytoskeleton and junction proteins [71–73]. In our study, we found that GDNPs 2 affected the expression of numerous cytoskeleton proteins, including adseverin, cofillin-1, KRT19 (keratin, type I cytoskeletal 19), KRT78 (keratin 78 type II), and the adherens junction protein, desmoglein.…”

Section: Discussionmentioning

confidence: 58%

Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer

et al. 2016

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There is a clinical need for new, more effective treatments for chronic and debilitating inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. In this study, we characterized a specific population of nanoparticles derived from edible ginger (GDNPs 2) and demonstrated their efficient colon targeting following oral administration. GDNPs 2 had an average size of ~230 nm and exhibited a negative zeta potential. These nanoparticles contained high levels of lipids, a few proteins, ~125 microRNAs (miRNAs), and large amounts of ginger bioactive constituents (6-gingerol and 6-shogaol). We also demonstrated that GDNPs 2 were mainly taken up by intestinal epithelial cells (IECs) and macrophages, and were nontoxic. Using different mouse colitis models, we showed that GDNPs 2 reduced acute colitis, enhanced intestinal repair, and prevented chronic colitis and colitis-associated cancer (CAC). 2D-DIGE/MS analyses further identified molecular target candidates of GDNPs 2 involved in these mouse models. Oral administration of GDNPs 2 increased the survival and proliferation of IECs and reduced the pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β), and increased the anti-inflammatory cytokines (IL-10 and IL-22) in colitis models, suggesting that GDNPs 2 has the potential to attenuate damaging factors while promoting the healing effect. In conclusion, GDNPs 2, nanoparticles derived from edible ginger, represent a novel, natural delivery mechanism for improving IBD prevention and treatment with an added benefit of overcoming limitations such as potential toxicity and limited production scale that are common with synthetic nanoparticles.

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Section: Discussionmentioning

confidence: 58%

Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer

et al. 2016

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“…Matrix metalloproteinase 9 and disintegrin and metalloproteinase domain containing protein 10 induce the cleavage of the DM cadherin desmoglein 2, resulting in the disruption of DM complexes and impaired intestinal epithelial-barrier function. 120 …”

Section: Effects Of Inflammationmentioning

confidence: 99%

Inflammation and the Intestinal Barrier: Leukocyte–Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair

2016

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The intestinal tract is lined by a single layer of columnar epithelial cells that forms a dynamic, permeable barrier allowing for selective absorption of nutrients, while restricting access to pathogens and food-borne antigens. Precise regulation of epithelial barrier function is therefore required for maintaining mucosal homeostasis and depends, in part, on barrier-forming elements within the epithelium and a balance between pro- and anti-inflammatory factors in the mucosa. Pathologic states, such as inflammatory bowel disease, are associated with a leaky epithelial barrier, resulting in excessive exposure to microbial antigens, recruitment of leukocytes, release of soluble mediators, and ultimately mucosal damage. An inflammatory microenvironment affects epithelial barrier properties and mucosal homeostasis by altering the structure and function of epithelial intercellular junctions through direct and indirect mechanisms. We review our current understanding of complex interactions between the intestinal epithelium and immune cells, with a focus on pathologic mucosal inflammation and mechanisms of epithelial repair. We discuss leukocyte–epithelial interactions, as well as inflammatory mediators that affect the epithelial barrier and mucosal repair. Increased knowledge of communication networks between the epithelium and immune system will lead to tissue-specific strategies for treating pathologic intestinal inflammation.

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“…99,104,114 Inflammation-induced alterations in expression of apical junctional complex proteins are not specific to tight and adherens junctions structures because disruption of intestinal epithelial desmosomal structure during inflammation has also been shown to have potent functional consequences. 115 However, in contrast to the decreased protein expression observed for tight junction molecules, unpublished studies suggest that expression of the desmosomal cadherin desmoglein 2 (Dsg2) may be increased under certain inflammatory conditions. Furthermore, exposure of intestinal epithelial cells to inflammatory cytokines or products from migrating neutrophils results in MMP-9 and ADAM 10-dependent cleavage and shedding of the extracellular domain of Dsg2.…”

Section: Neutrophil-epithelial Interactionsmentioning

confidence: 99%

“…Shed Dsg2 ectodomains likely compete with heterotypic binding between desmosomal cadherins disrupting desmosomal structure and cell-cell contacts. 115 In addition, cleaved Dsg2 ectodomains have also been shown to interact with growth factor receptors HER2/HER3, resulting in activation of Akt/mammalian target of rapamycin and mitogen-activated protein kinase signaling pathways to promote intestinal epithelial cell proliferation and mucosal homeostasis. Similarly, release of elastase from migrating neutrophils has been shown to cleave E-cadherin, resulting in b-cateninedependent signaling events and subsequent proliferative signals.…”

Section: Neutrophil-epithelial Interactionsmentioning

confidence: 99%

Neutrophil-Epithelial Interactions

Parkos

2016

The American Journal of Pathology

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Inflammation-induced desmoglein-2 ectodomain shedding compromises the mucosal barrier

Cited by 46 publications

References 75 publications

Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer

Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer

Inflammation and the Intestinal Barrier: Leukocyte–Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair

Neutrophil-Epithelial Interactions

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