STAT6-Mediated Keratitis and Blepharitis: A Novel Murine Model of Ocular Atopic Dermatitis

Turner, Matthew J.; DaSilva-Arnold, Sonia; Luo, Na; Hu, Xinyao; West, Callah C.; Sun, Lou; Hall, Charles E.; Bradish, Joshua R.; Kaplan, Mark H.; Travers, Jeffrey B.; Sun, Yan

doi:10.1167/iovs.13-13685

Cited by 14 publications

(12 citation statements)

References 18 publications

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“…These mice, termed Stat6VT transgenic mice, have T cell-specific expression of a constitutively active Stat6 protein derived by mutating V-547 and T-548 to alanine (Bruns et al , 2003; Daniel et al , 2000). Transgenic mice have increased Th2 cell development, increased serum IgE concentrations, and develop spontaneous allergic inflammation in tissues around the eye, in the lung, and in the skin (Sehra et al , 2008a; Sehra et al , 2010; Turner et al , 2014). The skin of Stat6VT mice has slower recovery from injuries including treatment with retinoic acid, detergent and vitamin D analogs (DaSilva et al , 2012; Sehra et al , 2010; Turner et al , 2013), and is more susceptible to infection (Howell et al , 2011).…”

Section: Introductionmentioning

confidence: 99%

Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation

Sehra

Serezani

Ocaña

et al. 2016

Journal of Investigative Dermatology

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Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by infiltration of eosinophils, T helper cells and mast cells. The role of mast cells in AD is not completely understood. To define the effects of mast cells on skin biology, we observed that mast cells regulate the homeostatic expression of Epidermal Differentiation Complex (EDC) and other skin genes. Decreased EDC gene expression in mice that genetically lack mast cells (KitW-sh/W-sh mice) is associated with increased uptake of protein antigens painted on the skin by dendritic cells, compared to similarly treated wild-type mice, suggesting a protective role for mast cells in exposure to nominal environmental allergens. To test this further, we crossed KitW-sh/W-sh mice with Stat6VT transgenic mice that develop spontaneous AD-like disease that is dependent on Th2 cytokines and associated with high serum concentrations of IgE. We observed that Stat6VT x KitW-sh/W-sh mice developed more frequent and more severe allergic skin inflammation than Stat6VT transgenic mice that had mast cells. Together, these studies suggest that mast cells regulate epidermal barrier function and have a potential protective role in the development of AD-like disease.

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Section: Introductionmentioning

confidence: 99%

Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation

Sehra

Serezani

Ocaña

et al. 2016

Journal of Investigative Dermatology

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“…Stat6VT mice on C57BL/6 and SKH1 backgrounds have previously been described and develop an AD-like phenotype [7, 43, 44, 51, 52]. The Stat6VT transgene includes the human CD2 locus control region directing expression of the human Stat6 coding sequence with V547 and T548 mutated to alanine such that T cells express a constitutively active Stat6 mutant protein.…”

Section: Methodsmentioning

confidence: 99%

“…Ocular and periocular (i.e. blepharitis, keratitis and uveitis) AD-like disease phenotypes also occur in these mice [43, 44, 52]. Histologic features of AD-like lesions include acanthosis and spongiosis and a perivascular and interstitial lymphocyte- and eosinophil-rich inflammatory cell infiltrate.…”

Section: Introductionmentioning

confidence: 99%

“…The Stat6VT model also mirrors several other aspects of human AD including the following: 1) disease develops spontaneously (i.e. it does not require exposure to environmental allergens, irritants or other physical insults); 2) nonlesional skin exhibits baseline defects in epidermal barrier function; 3) recovery of epidermal barrier function following exposure to irritants is impaired; 4) disease is critically dependent on IL-4 and 5) disease is exacerbated by loss of function mutations in epidermal differentiation complex genes like Flg [12, 43–45, 47, 51, 52]. In contrast to many mouse models of AD that develop disease secondary to environmental exposures or genetic defects in keratinocytes, pathogenesis in the Stat6VT model is driven by a monogenic defect in the T cell compartment thus providing a model in which to study the ability of T cells to initiate AD pathogenesis [7, 43].…”

Section: Introductionmentioning

confidence: 99%

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Phenotyping acute and chronic atopic dermatitis-like lesions in Stat6VT mice identifies a role for IL-33 in disease pathogenesis

et al. 2018

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The Stat6VT mouse model of atopic dermatitis (AD) is induced by T-cell-specific expression of a constitutively active form of the protein signal transducer and activator of transcription 6 (STAT6). Although AD-like lesions are known to develop in Stat6VT mice, this study was designed to determine if these mice develop acute and chronic phases of disease similar to humans. To address this, AD-like lesions from Stat6VT mice were harvested at two different timepoints relative to their onset. Lesions harvested within 1 week after development were defined as acute lesions, and those present for 1 month or more were defined as chronic lesions. Acute and chronic AD-like lesions from Stat6VT mice exhibited histologic findings and cytokine expression patterns similar to acute and chronic AD lesions in humans. Further analysis revealed increased levels of interleukin (IL)-33 transcripts in AD-like lesions compared to Stat6VT nonlesional and wild-type skin controls. Immunofluorescence also revealed increased numbers of IL-33 keratinocytes in Stat6VT lesional skin and localized IL-33 keratinocytes to a keratin 5 subset. Furthermore, AD-like disease was more severe in IL-33-deficient Stat6VT mice compared to IL-33-sufficient Stat6VT mice. These studies suggest that Stat6VT mice can serve as a model of acute and chronic AD and that IL-33 may attenuate inflammation in this system.

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“…T cells from Stat6VT transgenic mice are predisposed to differentiate into Th2 cells both in vitro and in vivo . Stat6VT transgenic mice develop spontaneous allergic inflammation in the skin, lung and periocular mucosal tissue . The absence of IL‐4 in Stat6VT transgenic mice protects them from lung and skin inflammation and helps to restore barrier function and EDC gene expression, suggesting that IL‐4 is a critical effector cytokine .…”

Section: Introductionmentioning

confidence: 99%

Poly‐ADP ribose polymerase‐14 limits severity of allergic skin disease

et al. 2017

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Poly-ADP ribose polymerase-14 (PARP14 or ARTD8) was initially identified as a transcriptional co-activator for signal transducer and activator of transcription 6 (Stat6), where the presence of interleukin-4 (IL-4) and activated Stat6 induces the enzymatic activity of PARP14 that promotes T helper type 2 differentiation and allergic airway disease. To further our understanding of PARP14 in allergic disease, we studied the function of PARP14 in allergic inflammation of skin using mice that express constitutively active Stat6 in T cells (Stat6VT) and develop spontaneous inflammation of the skin. We mated Stat6VT mice to Parp14 mice and observed that approximately 75% of the Stat6VT × Parp14 mice develop severe atopic dermatitis (AD)-like lesions, compared with about 50% of Stat6VT mice, and have increased morbidity compared with Stat6VT mice. Despite this, gene expression in the skin and the cellular infiltrates was only modestly altered by the absence of PARP14. In contrast, we saw significant changes in systemic T-cell cytokine production. Moreover, adoptive transfer experiments demonstrated that decreases in IL-4 production reflected a cell intrinsic role for PARP14 in Th2 cytokine control. Hence, our data suggest that although PARP14 has similar effects on T-cell cytokine production in several allergic disease models, the outcome of those effects is distinct, depending on the target organ of disease.

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STAT6-Mediated Keratitis and Blepharitis: A Novel Murine Model of Ocular Atopic Dermatitis

Cited by 14 publications

References 18 publications

Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation

Mast Cells Regulate Epidermal Barrier Function and the Development of Allergic Skin Inflammation

Phenotyping acute and chronic atopic dermatitis-like lesions in Stat6VT mice identifies a role for IL-33 in disease pathogenesis

Poly‐ADP ribose polymerase‐14 limits severity of allergic skin disease

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