Diverse Regulation of Claudin-1 and Claudin-4 in Atopic Dermatitis

Gruber, Robert; Börnchen, Christian; Rose, Katharina; Daubmann, Anne; Volksdorf, Thomas; Wladykowski, Ewa; Vidal-y-Sy, Sabine; Peters, Eva M.J.; Danso, Mogbekeloluwa O.; Bouwstra, Joke A.; Hennies, Hans Christian; Moll, Ingrid; Schmuth, Matthias; Brandner, Johanna M.

doi:10.1016/j.ajpath.2015.06.021

Cited by 118 publications

(120 citation statements)

References 48 publications

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“…To test this, we examined the expression of RAPTOR, phosphorylated AKT, and filaggrin in the unaffected, nonlesional, nonflexural epidermis of 5 patients with early-onset severe AD and of 3 subjects without AD (Fig 1, A and B , and Table E1 in this article's Online Repository at www.jacionline.org). Nonlesional and nonflexural skin from patients with AD has been previously demonstrated to be barrier deficient and represented a way of investigating the disease before acute immune involvement 21, 22. Phosphorylated AKT was significantly downregulated on the protein level in unaffected AD skin sections.…”

Section: Resultsmentioning

confidence: 99%

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

Naeem¹,

Tommasi²,

Callebaut

et al. 2017

Journal of Allergy and Clinical Immunology

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BackgroundFilaggrin, which is encoded by the filaggrin gene (FLG), is an important component of the skin's barrier to the external environment, and genetic defects in FLG strongly associate with atopic dermatitis (AD). However, not all patients with AD have FLG mutations.ObjectiveWe hypothesized that these patients might possess other defects in filaggrin expression and processing contributing to barrier disruption and AD, and therefore we present novel therapeutic targets for this disease.ResultsWe describe the relationship between the mechanistic target of rapamycin complex 1/2 protein subunit regulatory associated protein of the MTOR complex 1 (RAPTOR), the serine/threonine kinase V-Akt murine thymoma viral oncogene homolog 1 (AKT1), and the protease cathepsin H (CTSH), for which we establish a role in filaggrin expression and processing. Increased RAPTOR levels correlated with decreased filaggrin expression in patients with AD. In keratinocyte cell cultures RAPTOR upregulation or AKT1 short hairpin RNA knockdown reduced expression of the protease CTSH. Skin of CTSH-deficient mice and CTSH short hairpin RNA knockdown keratinocytes showed reduced filaggrin processing, and the mouse had both impaired skin barrier function and a mild proinflammatory phenotype.ConclusionOur findings highlight a novel and potentially treatable signaling axis controlling filaggrin expression and processing that is defective in patients with AD.

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Section: Resultsmentioning

confidence: 99%

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

Naeem¹,

Tommasi²,

Callebaut

et al. 2017

Journal of Allergy and Clinical Immunology

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“…In this respect, the adaptive immune response is associated with increased levels of Th2 cytokines and IgE, which play central roles in the pathogenesis of AD. Moreover, recent papers suggest that inflammation causes Cldn1 to be down-regulated (9,28). The second hypothesis is that skin barrier defects increase the risk of developing AD.…”

Section: Discussionmentioning

confidence: 99%

“…The expression patterns of claudins vary according to cell type and contribute to a variety of paracellular barrier functions that specifically maintain the homeostasis of tissues and organs (4). In the skin, TJs are key contributors to the epidermal paracellular barrier, and claudin-1 (CLDN1), a main component of TJs in the epidermis, is reported to be indispensable for this barrier function; abnormalities in CLDN1 cause human skin diseases (5)(6)(7)(8)(9). However, because Cldn1 knock-out (KO) mice die within 1 d of birth due to dehydration (10,11), it has been difficult to study how Cldn1 contributes to skin diseases.…”

mentioning

confidence: 99%

Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

Tokumasu

Yamaga

Yamazaki

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

116

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Atopic dermatitis (AD) is a chronic inflammatory skin disease in humans. It was recently noted that the characteristics of epidermal barrier functions critically influence the pathological features of AD. Evidence suggests that claudin-1 (CLDN1), a major component of tight junctions (TJs) in the epidermis, plays a key role in human AD, but the mechanism underlying this role is poorly understood. One of the main challenges in studying CLDN1's effects is that Cldn1 knock-out mice cannot survive beyond 1 d after birth, due to lethal dehydration. Here, we established a series of mouse lines that express Cldn1 at various levels and used these mice to study Cldn1's effects in vivo. Notably, we discovered a dose-dependent effect of Cldn1's expression in orchestrating features of AD. In our experimental model, epithelial barrier functions and morphological changes in the skin varied exponentially with the decrease in Cldn1 expression level. At low Cldn1 expression levels, mice exhibited morphological features of AD and an innate immune response that included neutrophil and macrophage recruitment to the skin. These phenotypes were especially apparent in the infant stages and lessened as the mice became adults, depending on the expression level of Cldn1. Still, these adult mice with improved phenotypes showed an enhanced hapten-induced contact hypersensitivity response compared with WT mice. Furthermore, we revealed a relationship between macrophage recruitment and CLDN1 levels in human AD patients. Our findings collectively suggest that CLDN1 regulates the pathogenesis, severity, and natural course of human AD.claudin-1 | tight junctions | atopic dermatitis

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“…The claudin-1 level showed an inverse correlation with a high serum IgE level and eosinophilia. Claudin-1 expression was significantly suppressed by IL-4, IL-13 and IL-31 in a human skin equivalent [105]. While claudin-1 knockout is lethal, low claudin-1-expressing conditioned mice exhibited AD-like dermatitis and an increased recruitment of neutrophil and macrophage in the skin.…”

Section: Barrier Dysfunctionmentioning

confidence: 99%

Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis

Kim

Cho

et al. 2016

IJMS

110

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Atopic dermatitis (AD) is a multifactorial inflammatory skin disease resulting from interactions between genetic susceptibility and environmental factors. The pathogenesis of AD is poorly understood, and the treatment of recalcitrant AD is still challenging. There is accumulating evidence for new gene polymorphisms related to the epidermal barrier function and innate and adaptive immunity in patients with AD. Newly-found T cells and dendritic cell subsets, cytokines, chemokines and signaling pathways have extended our understanding of the molecular pathomechanism underlying AD. Genetic changes caused by environmental factors have been shown to contribute to the pathogenesis of AD. We herein present a review of the genetics, epigenetics, barrier dysfunction and immunological abnormalities in AD with a focus on updated molecular biology.

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Diverse Regulation of Claudin-1 and Claudin-4 in Atopic Dermatitis

Cited by 118 publications

References 48 publications

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

A mechanistic target of rapamycin complex 1/2 (mTORC1)/V-Akt murine thymoma viral oncogene homolog 1 (AKT1)/cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in patients with atopic dermatitis

Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

Molecular Mechanisms of Cutaneous Inflammatory Disorder: Atopic Dermatitis

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