# Skin Barrier Function: The Interplay of Physical, Chemical, and Immunologic Properties
## 5 Interleukins and Toll-like Receptors in Skin Barrier Regulation  
Multiple interleukins, such as IL-22, play a significant role in the regulation of the skin barrier [85]. IL-22 is part of the IL-10 cytokine family, is primarily produced by CD4+ T cells, and signals through the IL-22R heterodimer receptor [85; 86; 87]. Although IL-22 mainly reinforces skin barrier function by promoting inflammation, continuous, unregulated IL-22 expression causes unwanted inflammation [86]. This exaggerated inflammatory response further contributes to psoriasis and atopic dermatitis [86; 87]. Studies comparing patients afflicted with psoriasis to a control group show a significantly higher IL-22 expression in the psoriasis group [88]. Furthermore, IL-22 activity inhibits keratinocyte differentiation, contributing to the presentation of undifferentiated cells that is seen in psoriatic skin [89; 90; 91]. IL-22 also induces hyperproliferation of keratinocytes, further contributing to psoriatic skin lesions [92]. Additionally, mouse models show that the activation of IL-22 results in atopic dermatitis through an increased presence of CD4+ and CD8+ T cells, which induce inflammation [87]. Over-expression of IL-22 is therefore disruptive to normal skin barrier function. Accordingly, recent data suggest that targeting IL-22 may prove effective in treating psoriasis and other inflammatory conditions [88]. Solenopsin analogs S12 and S14 have been shown to downregulate IL-22, decreasing epidermal thickness and CD4+/CD8+ T cell infiltration [57]. IL-17 also plays a significant role in the disruption of a normal skin barrier. IL-17 is a proinflammatory cytokine that is expressed heavily in psoriatic skin [93]. IL-17 promotes inflammation by contributing to the buildup of neutrophils and by upregulating chemokines that are known to cause psoriasis [93]. Further, IL-17 has been found to downregulate IL-12, which is responsible for inducing IFN-gamma expression in Th1 cells [94]. Th1 cells play a crucial role in the cell immune response and protection from pathogens [95]. Therefore, by suppressing IL-12 expression, IL-17 inhibits both IFN-gamma expression and, subsequently, Th1 expression [94]. These conclusions, along with a recent trial showing promising results after reducing the IL-17 expression in patients with psoriasis, suggest that inhibiting the IL-17 family may effectively target psoriasis [93]. Although it is primary a driver of psoriasis, IL-17 assumes a more minor role in promoting atopic dermatitis [96]. IL-17 is expressed in atopic dermatitis lesions in relatively low concentrations [96]. Interestingly, IL-17's receptor A (IL-17 RA) seems to be positively correlated with skin barrier function. In mouse models of atopic dermatitis, IL-17 RA absence not only worsened, but also spontaneously caused inflammation [97]. It was concluded that mice lacking IL-17 RA have overall defective barriers with dysbiotic skin microbiomes [97]. Furthermore, this inflammation appeared to be mediated by a Th2 immune response and improved upon antibiotic treatment, showing that IL-17 RA expression could play a significant role in modulating an appropriate immune response and maintaining a healthy skin barrier [97]. Recent treatments that target IL-17, including brodalumab, izekizumab, and secukinumab, have shown clinical efficacy in the treatment of skin barrier disorders including psoriasis [98]. IL-12 is a key interleukin that was previously targeted as a treatment for psoriasis (with antibodies targeting both IL-12 and IL-23) [99]. However, more recent research has suggested a restorative role in the skin barrier for IL-12 [53; 100]. IL-12 was the first member that was discovered from the IL-12 cytokine family [101]. It has been implicated as a proinflammatory cytokine that promotes the production of IFN-gamma and stimulates the Th1 immune response [101; 102]. Despite being seen largely as a proinflammatory cytokine, there are certain contexts wherein IL-12 may limit inflammation and offer other benefits to skin barrier restoration [53; 57].