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

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.

Flightless I exacerbation of inflammatory responses contributes to increased colonic damage in a mouse model of dextran sulphate sodium-induced ulcerative colitis

“…Retrospective and prospective studies with UC patients have highlighted the importance of mucosal healing as the critical endpoint in disease management 27,28 . This study has shown that human UC lesions have significantly elevated levels of Flii, a cytoskeletal protein previously shown to impair healing responses and to be upregulated in response to tissue inflammation in a number of different inflammatory skin disease conditions including human psoriasis, dermatitis and inflammation mediated epidermolysis bullosa acquisita 20,21,24 . In the current study, Flii was prominent in the inflammatory infiltrate of human lamina propria surrounding the distal colon crypts suggesting its potential involvement in the inflammatory pathway of human colitis.…”

“…Plasma Flii binding to lipopolysaccharide alters macrophage activation and subsequent macrophage secretion of TNF-α 38 . Additionally, a recent study has shown that Flii alters inflammatory responses in inflammation mediated atopic dermatitis, where high Flii correlates with increased inflammatory responses resulting in a skewed Th 2 response 24 .…”

“…In contrast, Flii positively influences tissue regeneration in the context of Wnt signalling pathways during hair follicle regeneration and claw and digit tip regeneration 16,17 illustrating the diverse roles of this cytoskeletal protein. Importantly, Flii modulates TLR-4 mediated inflammatory responses 18,19 , augments Th 1 /Th 2 cell responses as well as autoantibody production and regulates inflammation in a number of inflammatory skin conditions including psoriasis, atopic dermatitis and epidermolysis bullosa acquisita 20–24 . Its function has not been investigated in the intestine.…”

Immunological Memory in Imiquimod-Induced Murine Model of Psoriasiform Dermatitis

“…The level of skin erythema was measured daily during each assessment cycle using the DermaLab Combo (Cortex Technology ApS, Hadsundm, Denmark). The mice were killed after each IMQ cycle/assessment cycle (acute group day 6, chronic group day 26, resolved group day 46) ( n = 8/group) and serum and skin collected for assessment of inflammation using histology and immunohistochemistry and for isolation of T cells for flow cytometry using established protocols [ 27 ].…”

Increasing the level of cytoskeletal protein Flightless I reduces adhesion formation in a murine digital flexor tendon model

“…Recent studies have further shown that explanted tendons from Flii overexpressing mice have significantly elevated tenocyte outgrowth compared to Flii +/− mice [20]. In addition, there is a large body of evidence showing the importance of Flii in cellular adhesion and matrix remodelling [21][22][23] as well as tissue inflammation during wound healing and in inflammatory skin conditions [24][25][26][27][28], consequently, here, we investigated the effect of altering Flii expression in vivo on tendon adhesion formation. A murine model of tendon adhesion was used in these studies and conducted using a partial laceration of the digital flexor tendon in the third and fourth digit of both hind-paws, in conjunction with a full tenotomy to immobilise the digits of the paw [29].…”