IL-25 in Atopic Dermatitis: A Possible Link between Inflammation and Skin Barrier Dysfunction?

Abstract

Atopic dermatitis (AD) is a common skin disease associated with a T(H)2 response and increased levels of T(H)2-associated cytokines and IgE. The mechanisms resulting in skewing the immune response in a T(H)2 direction in AD are not fully elucidated. However, such skewing has recently been associated with IL-25 in a murine model for allergic airway disease. The aim of this study was to investigate whether IL-25 may have a role in AD. We have identified IL-25-producing cells within the dermis of AD patients and propose that these cells are dendritic cells (DCs). This is supported by in vitro experiments that indicate that monocyte-derived DCs are capable of producing IL-25. As null mutations of filaggrin are associated with the development of an impaired skin barrier in AD, we investigated whether IL-25 affects filaggrin synthesis by keratinocytes. Using mRNA analysis, we have shown that IL-25 stimulation does indeed decrease filaggrin synthesis in cultured keratinocytes. These results suggest that IL-25 produced by DCs could have a dual role as both an inducer of the T(H)2 response and as an inhibitor of filaggrin synthesis, thereby directly affecting skin barrier function in AD patients.

Type-2 Innate Lymphoid Cells in Asthma and Allergy

“…Increased transcripts encoding IL-33 and IL-25 were also detected in the cells in acute lesional atopic dermatitis skin as compared with control subjects, and in vitro cultured human ILC2 released type-2 cytokines and amphiregulin in response to IL-33 stimulation. These data are consistent with the elevated IL33 mRNA reported previously in the lesional skin of patients with AD and, similarly, the detection of higher levels of IL-25 in patients with AD (46)(47)(48). Notably, IL-33, and to a lesser extent TSLP (but not IL-25), induced migration of skin-derived human ILC2 (45,49).…”

New insights in the pathogenesis of atopic dermatitis

“…IL-25 increases the expression of IL-5 and IL-13 in TSLP-DC-activated T cells (26). Immunohistochemical staining showed increased IL-25 + keratinocytes in AD lesions, as compared to nonlesional skin (27). There was also an increased infiltration of cells, which expressed IL-17Rh1, an IL-25 receptor, in AD lesions, as compared to nonlesional AD skin (27).…”

“…Immunohistochemical staining showed increased IL-25 + keratinocytes in AD lesions, as compared to nonlesional skin (27). There was also an increased infiltration of cells, which expressed IL-17Rh1, an IL-25 receptor, in AD lesions, as compared to nonlesional AD skin (27). However, the majority of IL-25 producers are likely DC, eosinophils, and basophils (26,27).…”

Epidermal tight junctions in health and disease

“…Numerous studies have demonstrated that several inflammatory mediators (e.g., IL4, IL13, IL25, IL17A and histamine) affect keratinocyte differentiation, most often leading to impaired barrier formation. [72][73][74][75] Studies on noncutaneous epithelium have established that inflammatory mediators are involved in TJ assembly and disassembly during inflammatory conditions, 76 and also in keratinocytes an influence of several cytokines on TJ proteins/function was described (see below). Whether these mediators directly affect epidermal TJs or whether it is an indirect effect via altered differentiation is an active area of research.…”