Academic literature on the topic 'Skin barrier'

Moisturizers are used in various types of dry skin disorders, but also by people with healthy skin. It is not unusual that use of moisturizers is continued for weeks, months, or even years. A number of moisturizers have been shown to improve the skin barrier function, while others to deteriorate it, but the reason for observed effects remains unknown. Further understanding of the mechanism by which long-term treatment with moisturizers influences the skin barrier would have clinical implications, as barrier-deteriorating creams may enhance penetration of allergens or irritants and predispose to dry skin and eczema, while barrier-improving ones could reduce many problems. The present research combined non-invasive techniques with analyses of skin biopsies, allowing studies of the epidermis at molecular and cellular level. Test moisturizers were examined on healthy human volunteers for their effect on the skin barrier, with regard to such factors as pH, lipid type, and presence of a humectant, as well as complexity of the product. After a 7-week treatment with the moisturizers, changes in transepidermal water loss, skin capacitance, and susceptibility to an irritant indicated a modified skin barrier function. Moreover, the mRNA expression of several genes involved in the assembly, differentiation and desquamation of the stratum corneum, as well as lipid metabolism, was altered in the skin treated with one of the moisturizers, while the other moisturizer induced fewer changes. In conclusion, long-term use of moisturizers may strengthen the barrier function of the skin, but also deteriorate it and induce skin dryness. Moisturizers have also a significant impact on the skin biochemistry, detectable at molecular level. Since the type of influence is determined by the composition of a moisturizer, more careful selection of ingredients could help to design moisturizers generating a desired clinical effect, and to avoid ingredients with a negative impact on the skin.

One of the most important roles of the skin is the formation of an effective barrier to prevent desiccation as well as to keep out foreign pathogens and allergens. This is a tightly regulated process and involves many structural proteins, lipids, enzymes and biochemical components. One of the proteins that has an indispensable role in barrier formation is filaggrin, which is encoded by the filaggrin gene (FLG) that lies within a cluster of epidermal genes known as the epidermal differentiation complex (EDC) on chromosome 1q21. Recent studies in Europe have shown that null mutations in FLG lead to the loss of the filaggrin protein; this is the underlying genetic cause of ichthyosis vulgaris (IV) and is a significant predisposing factor for atopic dermatitis (AD) and other atopic conditions such as asthma, allergic rhinitis and food allergy. In this thesis, the critical role of FLG-null mutations was examined and confirmed as a strong predisposing factor for AD in Singaporean Chinese patients. In addition, AD patients with FLG mutations also showed an increased susceptibility for recurrent skin infections. Interestingly, a diverse and wide spectrum of FLG-null mutations was identified in the Singaporean Chinese population, as opposed to the dominance of a few common FLG mutations in Europe. This result highlighted discrete genetic variations between different ethnic groups. FLG-null mutations were also shown to have significant gene modifying effects on other skin barrier genes such as steroid sulphatase gene (STS) to exacerbate the phenotype of X-linked ichthyosis (XLI). Next, the effect of FLG¬-null mutations on other complex conditions such as acne vulgaris and childhood peanut sensitisation was investigated but no significant association of FLG mutations with these diseases were observed in the Singaporean Chinese population. Lastly, a study was attempted to search for a candidate gene for psoriasis within the EDC, through the use of fine mapping techniques. With the advent of faster and cheaper next generation sequencing (NGS) in the near future, the quest for susceptibility factors in complex traits will increase in effectiveness and speed.

Atopic Dermatitis (AD) is a chronic inflammatory disease characterised by pruritus, hyperkeratosis, parakeratosis and dry skin. Association of filaggrin mutations with AD has been reported, however not all AD patients have filaggrin mutations suggesting other mechanisms give rise to the barrier defect present in AD. Akt1 activity is essential for cornified envelope formation and correct profilaggrin processing, although the functional role of Akt1 in these processes remains unclear. The aim of this study was to investigate the role of downstream targets of Akt1 signaling in profilaggrin processing and cornified envelope formation. Using shRNA to knock down Akt1 activity in rat epidermal keratinocyte cell lines, an in vitro organotypic model was created that phenocopies AD displaying hyperkeratosis, parakeratosis and impaired filaggrin processing. Results show that reduced Akt activity led to decreased lamin A/C degradation disrupting nuclear disintegration process giving rise to parakeratosis. HspB1 is reported to interact with filaggrin and also involved in filaggrin processing. Inhibition of Akt activity demonstrated a switch between HspB1-filaggrin to HspB1- actin interaction in the upper epidermis, which may interfere with filaggrin processing. Cathepsin H (Ctsh) was down regulated 4-fold in our Akt1 knockdown cultures and its expression co-localized with filaggrin in the granular layer of human epidermis. Filaggrin processing was impaired in Ctsh shRNA knockdown cell lines, and both Ctsh+/− and Ctsh−/− mice displayed hyperkeratosis and reduced filaggrin expression. Inhibition of RAPTOR (a component of mTORC1) has previously been reported to increase Akt1 activity. Raptor overexpression in REKs showed a decrease in Akt phosphorylation, Ctsh and filaggrin processing, and treatment with Rapamycin, an mTORC1 inhibitor, reverses these effects. In uninvolved AD skin, increase in RAPTOR correlated with decrease in both Akt phosphorylation and filaggrin expression. This thesis presents a novel mechanism where increase in RAPTOR can lead to a reduction in epidermal granular Akt1 phosphorylation leading to impaired filaggrin processing and barrier defects in AD.

Atopic dermatitis, AD (synonym eczema) is a chronic inflammatory skin disease. It affects between 10 to 20% of children and 1 to 3% of adults worldwide. It is an important cause of morbidity and is estimated to cost £465 million per annum to the UK. AD is part of a family of Th-2 driven diseases and is often the first of these atopic diseases to manifest. The development of AD is often followed by asthma and allergic rhinitis later in life (a phenomenon known as the ‘atopic march’). Up to 50% of moderate to severe AD cases have been associated with genetic mutations affecting the epidermal barrier protein filaggrin. Filaggrin aggregates keratin filaments during terminal keratinocyte differentiation, allowing normal epidermal stratification. The role of filaggrin in maintaining a functional skin barrier is further supported by a clinical study conducted by ourselves. This is the first clinical study on a European cohort (58 participants) which showed that FLG mutations were associated with experimentally demonstrable defects of skin barrier function (increased baseline transepidermal water loss), more so following exposure to a chemical irritant. However, the majority of patients with AD, especially the milder cases, do not have FLG mutations. Some of the wild-type patients in our study were noticed to have accumulation of the large filaggrin proprotein and a lack of filaggrin monomers, indicating defective proteolysis of profilaggrin into the functional monomers. Our study also found disproportionately raised protease inhibitory activities amongst the AD participants. This inappropriately raised protease inhibition may interfere with profilaggrin proteolysis, leading to the development of AD in some wild-type patients. Having demonstrated that deficiency of filaggrin monomers is associated with a defective skin barrier, we focused on the function of filaggrin in the skin and attempted to improve the skin barrier function. In addition to keratin aggregation, filaggrin constitutes the natural moisturizing factors in the epidermis following its natural breakdown into amino acids. We note that filaggrin is disproportionately rich in amino acid histidine, implying that this amino acid may have a particular significance in maintaining a functional epidermal barrier. Using an in-house skin-equivalent model, we have shown that by increasing the histidine content in the cell culture media, we could increase the expression of filaggrin monomers and reduce the penetration of a fluorescent dye into the skin-equivalents. The latter indicates improved barrier function. Finally, we conducted a pilot human study which showed that histidine, when applied to mechanically damaged skin in AD and healthy participants, was associated with a faster recovery of the skin barrier function. These studies suggest that histidine is of therapeutic benefits in AD. A histidine-based treatment may be developed as an alternative to current anti-inflammatory and immunosuppressive agents used to treat AD.