INVESTIGATIVE REPORT
19 Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Topical Glucose Induces Claudin-1 and Filaggrin Expression in a Mouse Model of Atopic Dermatitis and in Keratinocyte Culture, Exerting Anti-inflammatory Effects by Repairing Skin Barrier Function
Kiyoko YAMADA 1, 2, Kenji MATSUSHITA 2, 3, Jingshu WANG 3 and Takuro KANEKURA 1
1
Department of Dermatology, 2 Department of Longevity Oral Science, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, and 3 Department of Oral Disease Research, National Center for Geriatrics and Gerontology, Obu, Japan
Atopic dermatitis( AD) is a chronic inflammatory skin disease. Corticosteroids, which are widely used for AD treatment, have adverse effects, and alternative treatments are urgently needed. This study examined the effect of topical application of high-dose glucose on inflamed skin in a murine model of AD. High-dose glucose treatment on the ear reduced dermatitis scores and ear thicknesses in mite antigen-treated NC / Nga mice. The levels of thymus and activation-regulated chemokine( TARC), Th cytokines( interleukin( IL)-4, IL-5, IL-12, IL-13, and( interferon) IFN-γ), and IgE were decreased in the serum of high-dose glucose-treated mice. Expression of claudin-1 and filaggrin was reduced in the ear epithelium in the NC / Nga mice. However, the reduced expression was restored by topical treatment with high-dose glucose. High-dose glucose also induced the expression of claudin-1 and filaggrin in cultured human skin keratinocytes. Co-stimulation with IL-4, IL-13, and thymic stromal lymphoprotein downregulated the expression of filaggrin in culture. However, high-dose glucose treatment restored the reduced expression of filaggrin. These results suggest that high-dose glucose treatment suppresses inflammation in the skin lesions by improving the skin barrier function.
Key words: claudin-1; filaggrin; sugar; steroid; anti-inflammation; allergy reaction; cytokines; IgE; skin barrier; mouse model.
Accepted Oct 2, 2017; Epub ahead of print Oct 2, 2017 Acta Derm Venereol 2018; 98: 19 – 25.
Corr: Kenji Matsuhista, Department of Oral Disease Research, National Center of Geriatrics and Gerontology, 7-430 Morioka-machi, Obu, Aichi 747-8511, Japan. E-mail: kmatsu30 @ ncgg. go. jp; Takuro Kanekura, Department of Dermatology, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. E-mail: takurok @ m2. kufm. kagoshima-u. ac. jp
Atopic dermatitis( AD) is a chronic inflammatory skin disease characterized by increased IgE in serum, pruritic and relapsing eczematous skin lesions with a thickened epidermis, skin barrier defects, and infiltration of inflammatory cells, such as lymphocytes, eosinophils and mast cells( 1 – 3). Thymus and activation-regulated chemokine( TARC), interleukin( IL)-4, IL-5, and IL-13 produced by Th2 cells are strongly associated with the onset and development of AD( 4, 5). Th2 cells are associated with the acute phase of AD. On the other hand, Th1 cells, which produce IL-12 and interferon( IFN)-γ, contribute to the pathogenesis of the chronic phase of AD( 6, 7). Corticosteroids have frequently been used for AD treatment( 8). However, steroids have adverse effects in patients with AD( 9) and alternative treatments are therefore needed.
Glucose is a major source of energy for mammalian cells. Abnormally high levels of glucose in the blood, as observed in diabetes, are harmful to the body and lead to the development of chronic complications, such as prolonged inflammation and impaired wound healing( 10 – 13). However, topical application of sugars, such as honey and glycosaminoglycans, have wound-healing properties( 14, 15). Glucose, one of the main sugars in honey, promotes wound healing( 16 – 19). However, little is known about the effect of topical application of glucose on skin inflammation.
Recent reports suggest that declining epidermal barrier function influences the pathological characteristics of AD. Filaggrin is expressed in the granular layers as a > 400 kDa precursor protein, profilaggrin. Profilaggrin is cleaved into filaggrin monomers and N- and C-terminal peptides at the boundary of the stratum corneum and stratum granulosum. Filaggrin monomers are further degraded into natural moisturizing factors that are thought to maintain hydration of the upper stratum corneum and reduce the pH of the skin surface( 20, 21). Filaggrin with both null mutations and loss-of-function variations is significantly associated with the development of AD in the European population( 22). Tight junctions are also key contributors to the epidermal barrier, and claudin-1, which is a main component of tight junctions in the epidermis, is crucial for transepidermal water loss( TEWL) and skin barrier function. Claudin-1 is decreased in skin lesions of patients with AD, triggering skin inflammation( 23).
To determine how glucose improves skin inflammation, we examined the effect of topical application of high-dose glucose on the inflamed skin in a murine model of chronic AD. We focused on claudin-1 and filaggrin and examined the expression of these molecules after treatment with a high concentration of glucose in vitro and in vivo.
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica. doi: 10.2340 / 00015555-2807 Acta Derm Venereol 2018; 98: 19 – 25