Increased Th2 activity and diminished skin barrier function cooperate in allergic skin inflammation

Abstract

Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T-cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt−/−) develop severe atopic dermatitis lesions by 3-5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6-7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt−/− mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD.

Atopic dermatitis: A tale of two distinct pathomechanisms that make you itch

“…In addition, in human models it was found that both antimicrobial activity and skin barrier proteins are decreased in AD skin by Th2 in a Stat6-dependent manner [22,23]. Importantly, Sehra et al were unable to induce an AD-like phenotype in mice carrying the single FLG-mutation [26]. This seems in contrast with a previous publication in the same mouse strain, but in this study the AD-like phenotype was only observed in older mice [9].…”

“…The publication of Sehra et al in the current issue of this journal now further elucidates the interaction between systemic and local changes that are crucial for the development of AD and the nature of the adaptive immune signals [26]. In their mouse model, they combined mutations in FLG in Flaky tail mice with a T-cellspecific expression of constitutively active Stat6.…”

“…Leisten et al demonstrated that FLG-deficient mice needed an additional adaptive immunity signal to develop an ADlike phenotype. They found that FLG-deficient, Rag2-deficient mice were unable to develop skin inflammation [25].The publication of Sehra et al in the current issue of this journal now further elucidates the interaction between systemic and local changes that are crucial for the development of AD and the nature of the adaptive immune signals [26]. In their mouse model, they combined mutations in FLG in Flaky tail mice with a T-cellspecific expression of constitutively active Stat6.…”

“…The development of allergic inflammation in these Stat6VT mice was still dependent on endogenous . Mice solely carrying the constitutively active Stat6 mutation can develop an AD-like phenotype, but only in 40% of the mice and only after 6-7 months of age, while 90% of mice carrying the combined FLG/STAT6 mutations develop an AD-like phenotype within 3-5 months of age [26]. A remarkable finding in this study is that the FLG mutation alone did not result in an increased protein translocation in skin, but the STAT6 transgene did result in increased protein translocation.…”

“…involucrin). The earlier (developmental) FLG decrease is what worsens AD disease, in the presence of the Stat6VT transgene [26]. It is tempting to speculate that it is the Th2-driven effects on skin, more than a dysfunctional FLG protein, which is the most important step in the development of AD.…”