AUTHOR=Kopecki Zlatko , Stevens Natalie E. , Chong Heng T. , Yang Gink N. , Cowin Allison J. 

TITLE=Flightless I Alters the Inflammatory Response and Autoantibody Profile in an OVA-Induced Atopic Dermatitis Skin-Like Disease

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01833

DOI=10.3389/fimmu.2018.01833

ISSN=1664-3224

ABSTRACT=<p>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 <italic>Flii</italic> 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 <italic>Flii</italic> heterozygous (<italic>Flii<sup>+/−</sup></italic>), wild-type (<italic>Flii<sup>+/+</sup></italic>), and <italic>Flii</italic> transgenic (<italic>Flii<sup>Tg/Tg</sup></italic>) mice by epicutaneous exposure to OVA for 3 weeks; each week was separated by 2-week resting period. Reduced <italic>Flii</italic> 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 Th<sub>1</sub> response. In contrast, <italic>Flii</italic> over-expression lead to a Th<sub>2</sub> skewed response characterized by increased pro-inflammatory TNF-α cytokine production, Th<sub>2</sub> chemokine levels, and Th<sub>2</sub> cell numbers. Sera from OVA-induced AD skin-like disease <italic>Flii<sup>+/−</sup></italic> mice showed a decreased level of autoreactivity while sera from <italic>Flii</italic><sup>Tg/Tg</sup> 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.</p>