Abstract
Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease characterized by excessive inflammation and disrupted skin barrier function. Although the etiology of AD is not completely understood, clinical and basic studies suggest increasing involvement of autoantibodies against intracellular proteins. An actin remodeling protein, Flightless I (Flii), has been shown to promote development of inflammatory mediated skin conditions and impairment of skin barrier development and function. Here, we sought to determine the effect of altering Flii expression on the development of AD and its contribution to autoimmune aspects of inflammatory skin conditions. Ovalbumin (OVA)-induced AD skin-like disease was induced in Flii heterozygous (Flii+/−), wild-type (Flii+/+), and Flii transgenic (FliiTg/Tg) mice by epicutaneous exposure to OVA for 3 weeks; each week was separated by 2-week resting period. Reduced Flii expression resulted in decreased disease severity and tissue inflammation as determined by histology, lymphocytic, and mast cell infiltrate and increased anti-inflammatory IL-10 cytokine levels and a marked IFN-γ Th1 response. In contrast, Flii over-expression lead to a Th2 skewed response characterized by increased pro-inflammatory TNF-α cytokine production, Th2 chemokine levels, and Th2 cell numbers. Sera from OVA-induced AD skin-like disease Flii+/− mice showed a decreased level of autoreactivity while sera from FliiTg/Tg mice counterparts showed an altered autoantibody profile with strong nuclear localization favoring development of a more severe disease. These findings demonstrate autoimmune responses in this model of OVA-induced AD-like skin disease and suggest that Flii is a novel target, whose manipulation could be a potential approach for the treatment of patients with AD.
Highlights
Atopic dermatitis (AD) is one of the most common heterogeneous inflammatory skin diseases affecting 20% of children and 1–3% of adults worldwide [1]
Flightless I (Flii) homozygous (Flii−/−) mice are embryonic lethal [26]; using the OVA-induced AD-like skin mouse model, the severity of OVAinduced AD-like lesions was determined in response to different Flii gene levels in Flii heterozygous (Flii+/−), normal (Flii+/+), and Flii transgenic (FliiTg/Tg) mice
Spectrophotometric measurement of the redness of the OVA exposed skin showed that Fliideficient mice had significantly less erythema (Figure 1B) than wild-type and FliiTg/Tg counterparts at day 50 of the experiment
Summary
Atopic dermatitis (AD) is one of the most common heterogeneous inflammatory skin diseases affecting 20% of children and 1–3% of adults worldwide [1]. A broad spectrum of IgE targeting self-antigens have been identified in above 90% of severe AD patients and high-avidity IgG autoantibodies have been proposed as potential diagnostic markers for severe AD [5, 10,11,12]. The fact that these autoantibodies are associated with disease severity implicates their role in both humoral and cellular immunity in AD pathogenesis [5, 12]. While the presence of autoantibodies can have a protective role as natural autoantibodies [14], the presence of nuclear autoantibodies in AD has been suggested to lead to the continual provocation of the immune system contributing to the severity and chronicity of disease
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