Administration of poly(I:C) improved dermatophagoides farinae-induced atopic dermatitis-like skin lesions in NC/Nga mice by the regulation of Th1/Th2 balance

Abstract

Atopic dermatitis (AD) is characterized by a chronic and replapsing skin disease with Th2-dominant allergic inflammation. Poly(I:C) has been shown to have immunopotentiator properties, but its effect on AD has not been examined. In this study, the immunomodulatory effects of poly(I:C), using dermatophagoides farinae (Df)-induced AD-like skin lesions in NC/Nga mice, were investigated. The clinical scores were reduced significantly by the treatment with poly(I:C) at 25 and 50 μg/mouse. Histological analysis of the skin also revealed that treatment of poly(I:C) at 25 and 50 μg/mouse significantly reduced the inflammatory cellular infiltrate, including mast cells and eosinophils. Moreover, poly(I:C) increased the level of IFN-γ, a Th1 cytokine, whereas decreasing that of selective Th2 cytokine both in vivo and in vitro. The levels of serum IgE and Th2 chemokines such as eotaxin, TARC, in spleen cells were also reduced by poly(I:C). These results suggest that poly(I:C) inhibit the development of Df-induced AD-like skin lesions in NC/Nga mice through regulation of the Th1/Th2 balance. Therefore, our results indicate that poly(I:C) might be a useful immunomodulatory agent for the treatment of human AD.

Introduction

Atopic dermatitis (AD) is chronically relapsing, non-contagious, and pruritic skin disorder with allergic inflammation [1], [2]. AD is caused by the complex interaction of genetic, pharmacological, environmental and psychological factors that result in the imbalance of immune system [3], [4]. Dysregulated T-helper 1 (Th1) and T-helper 2 (Th2) responses characterized by Th2-dominant allergic inflammation are thought to be central to the pathology of diseases such as AD and asthma [5], [6]. Particularly, Th2 immune responses mediated by interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13) are key to the pathogenesis of atopic disorders [7]. The presence of blood eosinophilia and increased serum IgE levels in the majority of patients with AD supports Th2 dominance in AD [8]. Some studies have demonstrated that interferon-gamma (IFN-γ), a Th1 cytokine, suppresses the production IgE by B cells, as well as the production of Th2 cytokine from Th2 cells [9], [10]. Therefore, it is important to consider the balance of Th1/Th2 cytokine in patients with immune diseases in allergic diseases such as AD.

NC/Nga mice spontaneously develop AD-like skin lesions under conventional condition, but not under specific pathogen-free (SPF) condition [11]. SPF NC/Nga mice treated with mite antigens develop clinical, immunological, and histological changes similar to those of AD patients, including an increase of number of mast cells and eosinophils degranulation, lymphocytes infiltration, as well as Th2 chemokines and their receptors [12], [13]. Additionally, the level of immunoglobulin (Ig) E in the serum increases gradually [14]. Recently, we have reported that the pathophysiological features of dermatitis induced by the repeated application with mite dermatophagoides farinae (Df) extract ointment in NC/Nga mice [15]. These findings suggest the possible involvement of Th2 cells in the development of AD in NC/Nga mice.

The immunopotentiator polyinosinic–polycytidylic acid [poly(I:C)], a synthetic analog of double-stranded RNA, leads to the activation of antigen presenting cells (APCs) such as B cells, dendritic cells (DCs), and macrophage through toll-like receptor (TLR) 3-mediated signaling [16]. Signaling through TLR3 leads to the secretion of proinflammatory of cytokine such as IL-12, IL-15, IL-18, and IFN-γ [17], [18], [19]. In addition, poly(I:C) has been used as an adjuvant in several pre-clinical studies for prevention vaccines [20], [21] and therapeutic cancer vaccines [22], [23]. Thus, poly(I:C) are being used as immunomodulatory agents because they could be able to shift Th1 responses from Th2 responses by activating the innate immune responses. Poly(I:C) have been shown to stimulate production of IL-12, IFN-γ in host cells [24], [25] and down-regulate Th2 responses in experimental animal models of allergic airway inflammation [26], [27]. Accordingly, it is conceivable that poly(I:C) could regulate the balance of Th1/Th2 cytokine production.

The goal of this study was to investigate the effects of poly(I:C) vaccine on changes of immune responses in the development of Df-induced dermatitis of NC/Nga mice, a condition histologically and clinically similar to human AD. The results showed that poly(I:C) vaccine improved the symptoms associated with dermatitis, reducing IgE, suppressing Th2-mediated cytokines and chemokines, at least in part, as a result of enhancement of IFN-γ-dominated Th1 responses.