Atopic dermatitis
AD is a complex chronic inflammatory skin disease that is associated with skin barrier defects and the activation of immune responses in the skin by environmental allergens and/or intrinsic factors.30 Although type 2 inflammatory responses and elevated IgE are known as the main characteristics of AD, some patients actually develop stronger T helper cell (Th) Th17/Th22 responses31. Among other characteristic features, activation of keratinocytes with some similarities to another inflammatory skin disease, psoriasis, plays an important role in AD30,32. Research on miRNAs in AD started with an array analysis of lesional skin samples from AD and psoriasis patients. The results of this early study suggested that alterations in miRNA levels in the skin of AD patients partially overlapped with that of psoriatic skin and include multiple miRNAs shown to be modulated in other inflammatory conditions33. For example, miR-21 and miR-146a were shown to be upregulated in the skin of psoriasis and AD patients33, of which miR-21 function in airway inflammation is discussed in other sections of this review. miR-146a was demonstrated to inhibit many pro-inflammatory chemokines in keratinocytes through targeting multiple factors of the NFκ-B pathway34-37 and miR-146a-deficient mice developed stronger inflammation in both AD and psoriasis models36,38. On the other hand, it has been shown that miR-146a deficiency in mice leads to a defect in IgE production39,40and is linked to a type 1/type 17 skewing phenotype41. However, as a negative relationship between miR-146a and IgE levels in patient serum samples was detected39. It appears that miR‐146a is needed for the production of IgE and suppression of type 1/17‐cell‐mediated immune responses in mice. Therefore, the increased expression of miR‐146a in the case of allergic inflammation might have limited influence on type‐2 cell‐mediated immune responses in a subgroup of AD patients with increased IgE.
Another miRNA that may influence the development of AD through its function in the immune system is miR-155. It was shown that miR-155 is overexpressed in the skin of AD patients, most likely due to infiltrating immune cells, and suggested that miR-155 may influence the development of AD through the downregulation of cytotoxic T lymphocyte-associated antigen 4 (CTLA4), a negative regulator of T cell activation37. In addition, it was reported that miR-155 expression positively correlated with AD severity, the number of Th17 cells and IL-17 mRNA expression and plasma concentration, indicating that miR-155 may influence the pathogenesis of AD through its effect on differentiation and function of Th17 cells42. The expression changes and effects in cell cultures of other miRNAs, including miR-151a43, -143, -124 and 10a are reported and outlined in Table 1 . Altogether, the studies of miRNAs in AD clearly demonstrate that miRNAs affect the severity of skin inflammation, modulate cellular responses of keratinocytes and specialized immune cells and thereby influence the pathogenesis of AD.