Effects of zinc deficient diet on development of atopic dermatitis-like eruptions in DS-Nh mice

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Summary

Background

Zinc is one of the essential dietary factors and zinc deficiency diminishes the immune system. However, the mechanisms by which zinc deficiency affects the immune system are not fully understood.

Objective

We analyzed the mechanisms of zinc deficiency affecting the allergic response using a DS-Nh mouse model of atopic dermatitis.

Methods

Male DS-Nh mice were fed a zinc deficient diet for 4 weeks. We measured transepidermal water loss (TEWL) and epidermal moisture level, assessed the skin eruption score, and examined the frequency of lymphocyte subpopulation in spleen and thymus by flow cytometry. The suppressive effect of CD25+CD4+ T cells was analyzed in vitro. The amount of cytokines produced by the spleen cells and the serum IgE levels were measured by ELISA.

Results

In DS-Nh mice fed the zinc deficient diet, skin eruptions were exacerbated and serum IgE levels and number of S. aureus on the skin surface was increased. IFN-γ and IL-13 production by spleen cells was increased. The number of CD25+CD4+ T cells in spleen was significantly decreased, while the percentage of Foxp3 positive cells in the CD25+CD4+ T cells was comparable to those of the controls. CD25+CD4+ T cells from mice fed the zinc deficient diet maintained a suppressive function compared with those from the controls.

Conclusion

These findings indicate that zinc deficiency influences the skin barrier system and immune system, and suggests that zinc deficiency acts as an exacerbation factor of atopic dermatitis.

Introduction

Atopic dermatitis (AD) in humans is a chronic pruritic inflammatory disease that fluctuates with remissions and progressions. The cause of AD is multifactorial involving immunological abnormalities and physiological and biochemical defects of the skin barrier structure [2], [3], [4], [5], [6]. There are a large number of reports of immunological abnormalities among AD patients, such as peripheral blood mononuclear cells (PBMC) producing Th2-type cytokines including IL-4, IL-5 and IL-10 when stimulated with specific antigens in vitro. [7]. In acute AD lesions, the ratio of IL-4 producing cells versus IFN-γ producing cells is increased and mononuclear cells from patients with AD produce larger amounts of IL-4, IL-5 and IL-13 compared to those from healthy individuals [3], [8]. On the other hand, chronic AD skin lesions have significantly fewer IL-4 and IL-13 mRNA-expressing cells but increased numbers of IL-5, IL-12 and IFN-γ mRNA-expressing cells compared to those in acute AD skin lesions. It is thought that IL-12 production by infiltrating macrophages results in switching to a Th1-type milieu associated with increased IFN-γ expression [3].

DS-Nh mice housed under conventional conditions, but not under specific pathogen-free (SPF) conditions, spontaneously developed AD-like dermatitis [9], [10]. The DS-Nh mouse strain originated from a mutant male mouse with deficient hair growth in an inbred DS strain colony at Aburahi Laboratories (Shionogi Co. Ltd., Shiga, Japan) in 1976. In this strain, elevation of serum IgE is detected from around 17 weeks of age [9], and increases in eosinophils and mast cells are also observed in the skin lesions [10]. Over the course of time, the affected mice develop severe lesions including splenomegaly and lymphadenopathy [9]. An increase in Staphylococcus aureus on the skin surface occurs under conventional conditions even before the appearance of eruptions. This increase in skin S. aureus is thus believed to play an important role in the induction of dermatitis in these mice. This is supported by the finding that the application of S. aureus to the skin of mice raised under SPF conditions induces dermatitis [9], [10].

The prevalence of allergic diseases has increased in many countries over recent decades, indicating that environmental exposure plays an important role in the etiology of these diseases. Dietary change is one of several causal factors in these trends. Zinc is one of the essential dietary factors and is present in all organs, tissues and body fluids. Zinc is also known as a non-redox active ion and is essential for cell growth, development and differentiation. Zinc functions mainly as a cofactor for cellular proteins, nucleic acids, carbohydrates and lipids. The total body zinc content of human subjects is 1.5–2.5 g and 6% of total zinc content exists in skin [12]. The plasma zinc pool (0.1%) is a minor pool, but is nevertheless highly mobile and immunologically important. A decreased plasma zinc pool has been reported in AD patients [1], and zinc deficiency diminishes the immune system [1]. However, the mechanisms by which zinc deficiency affects the immune system, and especially the allergic response, are not fully understood. In this study, we investigated the mechanisms of zinc deficiency affecting the allergic response using DS-Nh mice.

Section snippets

Animals and diet

Five-week-old male DS-Nh mice raised under SPF conditions were provided by Aburahi Laboratories. The DS-Nh mice used for this study were obtained as F1 (Nh/+) from male DS-Nh (Nh/Nh) × female DS (+/+) crosses. Mice were maintained under conventional conditions throughout this study.

Zinc deficient diet was purchased from Oriental Yeast Co. Ltd. (Tokyo, Japan). The mice were fed a powdered zinc deficient diet or control diet from 6 to 10 weeks of age (n = 3 per group). The control diet differed from

Appearance of AD-like skin lesions in DS-Nh mice fed the zinc deficient diet

To examine the effects of zinc deficiency on AD-like skin lesions, 6-week-old DS-Nh mice were fed the zinc deficient or control diet for 4 weeks. After 10 weeks of age, compared to mice fed the control diet, those fed the zinc deficient diet showed wider and more severe skin lesions (Fig. 1a), with erythema and erosion simultaneously observed on the neck, face, and cervical dorsum (Fig. 1b). Both groups ate similar amounts of food. To quantify the dry skin symptoms, we measured TEWL and

Discussion

In the present study, DS-Nh mice fed the zinc deficient diet had exacerbated skin lesions accompanied by increased serum IgE levels. Impairment of skin barrier and increased colony numbers of S. aureus on the skin surface can contribute to mechanism of this phenomenon. DS-Nh mice fed zinc deficient diet have also had a Th1/Th2 imbalance, since IFN-γ and IL-13 production by spleen cells stimulated with SEB and ConA significantly increased. These suggest that zinc deficiency acts as an

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