Barrier Function in Transgenic Mice Overexpressing K16, Involucrin, and Filaggrin in the Suprabasal Epidermis
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Available from: Steven Leach
- "Filaggrin is a structural barrier protein in skin keratinocytes; down-regulation of this protein has been implicated in the impairment of esophageal barrier function and development of atopic dermatitis (76). Filaggrin is a member of the epithelial differentiation cluster (EDC), and together with involucrin (another EDC member), prevents the proteolytic destruction of keratin during differentiation of epidermal cells (77, 78). This forms an important barrier function in cornified epithelial cells, although its function in esophageal epithelial cells is less clear. "
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ABSTRACT: Eosinophilic esophagitis (EoE) is an emerging disease characterized by esophageal eosinophilia (>15eos/hpf), lack of responsiveness to acid-suppressive medication and is managed by allergen elimination and anti-allergy therapy. Although the pathophysiology of EoE is currently unsubstantiated, evidence implicates food and aeroallergen hypersensitivity in genetically predisposed individuals as contributory factors. Genome-wide expression analyses have isolated a remarkably conserved gene-expression profile irrespective of age and gender, suggesting a genetic contribution. EoE has characteristics of mainly TH2 type immune responses but also some TH1 cytokines, which appear to strongly contribute to tissue fibrosis, with esophageal epithelial cells providing a hospitable environment for this inflammatory process. Eosinophil-degranulation products appear to play a central role in tissue remodeling in EoE. This remodeling and dysregulation predisposes to fibrosis. Mast-cell-derived molecules such as histamine may have an effect on enteric nerves and may also act in concert with transforming growth factor-β to interfere with esophageal musculature. Additionally, the esophageal epithelium may facilitate the inflammatory process under pathogenic contexts such as in EoE. This article aims to discuss the contributory factors in the pathophysiology of EoE.
Frontiers in Pediatrics 05/2014; 2:41. DOI:10.3389/fped.2014.00041
Available from: Matthias Schäfer
- "These encode the secretory leukocyte peptidase inhibitor (Slpi), the small proline rich proteins (Sprr) 2d and Sprr2h, keratin 16 (K16), cytochrome P450 family 2 subfamily b polypeptide 19 (Cyp2b19) and peroxisome proliferator activator receptor beta/delta (PPARb/d). K16 is upregulated in sulforaphane treated skin (Kerns et al, 2007), and overexpression of K16 in a transgenic mouse model resulted in hyperkeratosis and barrier disturbance (Presland et al, 2004). However, there was only a transient postnatal upregulation of K16 in K5cre-CMVcaNrf2 transgenic mice as determined by immunofluorescence staining (Fig S1E of "
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ABSTRACT: The skin provides an efficient permeability barrier and protects from microbial invasion and oxidative stress. Here, we show that these essential functions are linked through the Nrf2 transcription factor. To test the hypothesis that activation of Nrf2 provides skin protection under stress conditions, we determined the consequences of pharmacological or genetic activation of Nrf2 in keratinocytes. Surprisingly, mice with enhanced Nrf2 activity in keratinocytes developed epidermal thickening, hyperkeratosis and inflammation resembling lamellar ichthyosis. This resulted from upregulation of the cornified envelope proteins small proline-rich proteins (Sprr) 2d and 2h and of secretory leukocyte peptidase inhibitor (Slpi), which we identified as novel Nrf2 targets in keratinocytes. Since Sprrs are potent scavengers of reactive oxygen species and since Slpi has antimicrobial activities, their upregulation contributes to Nrf2's protective function. However, it also caused corneocyte fragility and impaired desquamation, followed by alterations in the epidermal lipid barrier, inflammation and overexpression of mitogens that induced keratinocyte hyperproliferation. These results identify an unexpected role of Nrf2 in epidermal barrier function, which needs to be considered for pharmacological use of Nrf2 activators.
→See accompanying article http://dx.doi.org/10.1002/emmm.201200223
EMBO Molecular Medicine 05/2012; 4(5):364-79. DOI:10.1002/emmm.201200219 · 8.67 Impact Factor
Available from: Sara J Brown
- "Each of these components has a different function in the differentiating epidermis. The S100-like calcium-binding domain (Markova et al., 1993) may have a role in the regulation of calcium-dependent events during terminal epidermal differentiation (Presland et al., 1992; Nirunsuksiri et al., 1995) or, conversely, calcium may be involved in the control of profilaggrin processing (Presland et al., 2004; Sandilands et al., 2009). The N-terminal domain is cleaved from profilaggrin and translocates to the nucleus where it may have a role in the enucleation of keratinocytes in the outer stratum corneum (Sandilands et al., 2009). "
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ABSTRACT: The discovery, in 2006, that loss-of-function mutations in the filaggrin (FLG) gene are the cause of ichthyosis vulgaris-the most common disorder of keratinization-and also a strong genetic risk factor for atopic eczema, marked a significant breakthrough in the understanding of eczema pathogenesis. Subsequent investigations of the role of FLG-null mutations have identified a series of significant associations with atopic disease phenotypes, including atopic asthma, allergic rhinitis, and peanut allergy. However, many questions remain to be answered in relation to the precise mechanisms by which deficiency of an intracellular protein expressed primarily in the differentiating epidermis may contribute to the development of cutaneous and systemic pathology. This review aims to highlight the key milestones in filaggrin research over the past 25 years, to discuss the mechanistic, clinical, and therapeutic implications, and to consider possible future directions for ongoing investigation.
Journal of Investigative Dermatology 12/2011; 132(3 Pt 2):751-62. DOI:10.1038/jid.2011.393 · 7.22 Impact Factor
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